JP6848047B2 - Spiroindron polyethylene glycol carbonate-based compound and its composition, preparation method and its use - Google Patents
Spiroindron polyethylene glycol carbonate-based compound and its composition, preparation method and its use Download PDFInfo
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- JP6848047B2 JP6848047B2 JP2019507118A JP2019507118A JP6848047B2 JP 6848047 B2 JP6848047 B2 JP 6848047B2 JP 2019507118 A JP2019507118 A JP 2019507118A JP 2019507118 A JP2019507118 A JP 2019507118A JP 6848047 B2 JP6848047 B2 JP 6848047B2
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- 229920001223 polyethylene glycol Polymers 0.000 title claims description 43
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- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 20
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Description
本発明は、医薬分野に属し、スピロインドロンポリエチレングリコールカーボネート系化合物及びその組成物、製造方法、及びその抗腫瘍活性のために抗癌剤としての使用に関する。 The present invention belongs to the pharmaceutical field and relates to a spiroindolone polyethylene glycol carbonate-based compound and its composition, a method for producing the same, and its use as an anticancer agent due to its antitumor activity.
癌は、ヒトの健康及び生命を脅す。近年、抗癌剤の研究は、特異的な分子標的治療薬の研究開発に転向している。
腫瘍抑制タンパク質p53は、腫瘍の発展の防止において重要な役割を果たす。約50%のヒトの癌では、p53タンパク質をコードする遺伝子が変異又は欠失を生じることによって、転写活性及び腫瘍抑制タンパク質の機能が不活性化される。残りの50%の場合、p53とヒト・マウス二重微小染色体2(MDM2)タンパク質との間での直接作用は、野生型p53の機能の阻害において重要な役割を果たす。小分子を用いてMDM2−p53間の相互作用を干渉することは、新たな癌治療の策略として考えられる。
Cancer threatens human health and life. In recent years, research on anti-cancer agents has turned to research and development of specific molecular-targeted therapeutic agents.
Tumor-suppressing protein p53 plays an important role in preventing tumor development. In about 50% of human cancers, mutations or deletions in the gene encoding the p53 protein inactivate transcriptional activity and tumor suppressor function. For the remaining 50%, direct action between p53 and the human-mouse double microchromosome 2 (MDM2) protein plays an important role in inhibiting the function of wild-type p53. Interfering with the interaction between MDM2-p53 using small molecules is considered as a new cancer treatment strategy.
2005年以来、王少萌らにより、MDM2−p53間の相互作用の阻害剤として、一連のスピロ−インドロン類似体が報告され、これら一連の化合物のうちの1つの化合物(SAR405838/MI−77301)が、現在、臨床開発段階に入った(US7759383B2、US8222288B2、US8680132B2、US20130030173A1、WO2012065022A2及びWO2012155066A2参照)。スイスのエフ・ホフマン・ラ・ロシュ社によりも、一連のスピロ−インドロン類似体(WO2011067185、WO2011134925及びWO2012022707参照)及び一連のピロリジン類似体(WO2013178570、WO2014206866及びWO2015000945)が報告され、そのうち、ピロリジン類似体のうちのRG7388が臨床開発段階に入った。これらの化合物は、溶解性に制限があることが確認されたので、体内及び臨床研究において、安定的な製剤の開発が大きな挑戦に直面する。 Since 2005, Wang Xiao Moe has reported a series of Spiro-Indolone analogs as inhibitors of the interaction between MDM2-p53, one of these series of compounds (SAR405838 / MI-77301). Has now entered the clinical development stage (see US7759383B2, US822228B2, US868132B2, US2013030173A1, WO20120652A2 and WO2012155066A2). The Swiss company F. Hoffmann La Roche also reported a series of spiro-indron analogs (see WO2011067185, WO2011134925 and WO201222707) and a series of pyrrolidine analogs (WO2013178570, WO20142068666 and WO201550000945), of which pyrrolidine analogs. Of these, RG7388 has entered the clinical development stage. Since these compounds have been confirmed to have limited solubility, the development of stable formulations faces great challenges in in vivo and clinical studies.
従来の化合物は、水溶性に劣るので、現在、経口製剤のみに用いられるが、深刻な胃腸影響があるので、バイオアベイラビリティが高くなく、臨床的腫瘍の治療効果に影響を及ぼす。このため、水溶性が良く、毒性が低く、静脈内注射用製剤に適用可能且つ活性がより高いスピロ−インドロンアナローグを、MDM2−p53相互作用の阻害剤として開発することが求められる。 Conventional compounds are currently used only in oral preparations because they are inferior in water solubility, but because of their serious gastrointestinal effects, they are not highly bioavailable and affect the therapeutic effect of clinical tumors. Therefore, it is required to develop a spiro-indron analog having good water solubility, low toxicity, applicability to intravenous injection preparations, and higher activity as an inhibitor of MDM2-p53 interaction.
そこで、本発明の目的は、水溶性が良く、毒性が低く、静脈内注射用製剤に適用可能且つ活性が高いスピロインドロンポリエチレングリコールカーボネート系化合物、その立体異性体又はその薬学的に許容される塩を提供することである。 Therefore, an object of the present invention is a spiroindolone polyethylene glycol carbonate-based compound having good water solubility, low toxicity, applicability to intravenous injection preparations, and high activity, a stereoisomer thereof, or a pharmaceutically acceptable compound thereof. To provide salt.
本発明の他の目的は、上記のスピロインドロンポリエチレングリコールカーボネート系化合物の調製方法を提供することである。
本発明の別の目的は、抗腫瘍医薬組成物を提供することである。
本発明のまた別の目的は、癌治療薬の調製における上記のスピロインドロンポリエチレングリコールカーボネート系化合物、その立体異性体又はその薬学的に許容される塩の使用を提供することである。
本発明のさらに別の目的は、癌の治療方法を提供することである。
Another object of the present invention is to provide a method for preparing the above-mentioned spiroindolone polyethylene glycol carbonate-based compound.
Another object of the present invention is to provide an antitumor pharmaceutical composition.
Another object of the present invention is to provide the use of the above-mentioned spiroindolone polyethylene glycol carbonate-based compounds, stereoisomers thereof or pharmaceutically acceptable salts thereof in the preparation of therapeutic agents for cancer.
Yet another object of the present invention is to provide a method of treating cancer.
本発明の一態様によれば、本発明は、下記の一般式Iで表されるスピロインドロンポリエチレングリコールカーボネート系化合物、その立体異性体又はその薬学的に許容される塩を提供する。
(I)
一般式Iにおいて、
Y1、Y2、Y3及びY4はそれぞれ独立してH及びハロゲンから選ばれ、
R1はH及びC1−C5アルキル基から選ばれ、
R2はH、C1−C5アルキル基及びC1−C5アルコキシ基から選ばれ、
R3はC1−C10アルキル基及びC2−C10アルケニル基から選ばれ、
nは1〜80の整数である。
According to one aspect of the present invention, the present invention provides a spiroindolone polyethylene glycol carbonate-based compound represented by the following general formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
(I)
In general formula I
Y 1 , Y 2 , Y 3 and Y 4 are independently selected from H and halogen, respectively.
R 1 is selected from H and C1-C5 alkyl groups
R 2 is selected from H, C1-C5 alkyl and C1-C5 alkoxy group,
R 3 is selected from the C1-C10 alkyl group and the C2-C10 alkenyl group.
n is an integer from 1 to 80.
本発明の他の態様によれば、本発明により提供される上記のスピロインドロンポリエチレングリコールカーボネート系化合物の製造方法は、下記の一般式IIIで表されるスピロインドロン系化合物と、下記の一般式IVで表される化合物とを、塩基の存在下で、求核置換反応させて、前記スピロインドロンポリエチレングリコールカーボネート系化合物を得るステップを含む。
(III)
(IV)
ここで、Y1、Y2、Y3、Y4、R1、R2、R3及びnは上記と同義である。
According to another aspect of the present invention, the method for producing the above-mentioned spiroindolone polyethylene glycol carbonate-based compound provided by the present invention includes the following spiroindolone-based compound represented by the general formula III and the following general. It comprises a step of subjecting a compound represented by the formula IV to a nucleophilic substitution reaction in the presence of a base to obtain the spiroindolone polyethylene glycol carbonate-based compound.
(III)
(IV)
Here, Y 1 , Y 2 , Y 3 , Y 4 , R 1 , R 2 , R 3 and n are synonymous with the above.
本発明の別の態様によれば、本発明により提供される抗腫瘍医薬組成物は、治療有効量の上記の一般式Iで表されるスピロインドロンポリエチレングリコールカーボネート系化合物、その立体異性体又はその薬学的に許容される塩及び1種又は複数の種類の薬学的に許容されるアジュバントを含む。 According to another aspect of the present invention, the antitumor pharmaceutical composition provided by the present invention is a therapeutically effective amount of a spiroindolone polyethylene glycol carbonate-based compound represented by the above general formula I, a stereoisomer thereof or a stereoisomer thereof. It comprises the pharmaceutically acceptable salt and one or more pharmaceutically acceptable adjuvants.
本発明のまた別の態様によれば、本発明は、癌治療薬の調製における一般式Iで表されるスピロインドロンポリエチレングリコールカーボネート系化合物、その立体異性体又はその薬学的に許容される塩の使用を提供する。 According to yet another aspect of the present invention, the present invention is a spiroindolone polyethylene glycol carbonate-based compound represented by the general formula I in the preparation of a therapeutic agent for cancer, a stereoisomer thereof or a pharmaceutically acceptable salt thereof. Provide use of.
本発明のさらに別の態様によれば、本発明は、治療有効量の一般式Iで表されるスピロインドロンポリエチレングリコールカーボネート系化合物、その立体異性体又はその薬学的に許容される塩を癌患者に投与する癌の治療方法を提供する。 According to yet another aspect of the present invention, the present invention cancers a therapeutically effective amount of a spiroindolone polyethylene glycol carbonate-based compound represented by the general formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. Provided is a method of treating cancer to be administered to a patient.
本発明のスピロインドロンポリエチレングリコールカーボネート系化合物、その立体異性体又はその薬学的に許容される塩は、優れた腫瘍阻害活性を有し、水溶性が良好であり、毒性が低く、静脈内注射用製剤に調製可能である。 The spiroindron polyethylene glycol carbonate compound of the present invention, its stereoisomer or a pharmaceutically acceptable salt thereof has excellent tumor inhibitory activity, has good water solubility, has low toxicity, and is injected intravenously. Can be prepared for use.
以下、本発明について具体的に説明する。
本発明のスピロインドロンポリエチレングリコールカーボネート系化合物、その立体異性体又はその薬学的に許容される塩によれば、好ましい実施形態において、前記スピロインドロンポリエチレングリコールカーボネート系化合物は、下記の一般式IIで表されるスピロインドロンポリエチレングリコールカーボネート系化合物であることが好ましい。
(II)
ここで、Y1、Y2、Y3、Y4、R1、R2及びnは上記と同義である。
Hereinafter, the present invention will be specifically described.
According to the spiroindolone polyethylene glycol carbonate-based compound of the present invention, its steric isomer or a pharmaceutically acceptable salt thereof, in a preferred embodiment, the spiroindolone polyethylene glycol carbonate-based compound is described in the following general formula II. It is preferably a spiroindolone polyethylene glycol carbonate-based compound represented by.
(II)
Here, Y 1 , Y 2 , Y 3 , Y 4 , R 1 , R 2 and n are synonymous with the above.
さらに好ましい実施形態において、
Y1、Y2、Y3及びY4は、それぞれ独立してH、F及びClから選ばれることが好ましい。
R1は、好ましくはH及びC1−C3アルキル基から選ばれ、また、より好ましくはメチル基又はエチル基、最も好ましくはメチル基である。
R2は、好ましくはC1−C5アルコキシ基から選ばれ、また、より好ましくはメトキシ基又はエトキシ基であり、最も好ましくはメトキシ基である。
R3は、好ましくはC1−C6アルキル基から選ばれ、また、より好ましくはペンチル基であり、最も好ましくはネオペンチル基である。
nは、好ましくは1〜60の整数、より好ましくは2〜50の整数、最も好ましくは3〜50の整数である。
In a more preferred embodiment
It is preferable that Y 1 , Y 2 , Y 3 and Y 4 are independently selected from H, F and Cl, respectively.
R 1 is preferably selected from H and C1-C3 alkyl groups, more preferably a methyl group or an ethyl group, and most preferably a methyl group.
R 2 is preferably selected from C1-C5 alkoxy group, and more preferably a methoxy group or an ethoxy group, most preferably a methoxy group.
R 3 is preferably selected from the C1-C6 alkyl group, more preferably a pentyl group, and most preferably a neopentyl group.
n is preferably an integer of 1 to 60, more preferably an integer of 2 to 50, and most preferably an integer of 3 to 50.
本発明に係る一般式Iで表されるスピロインドロンポリエチレングリコールカーボネート系化合物は、互変異性又は構造異性現象を示すことができる。これは、本発明がこれらの化合物のいずれかの互変異性型又は構造異性型、又はそれらの混合物を含み、且つ、上記の構造式で表されるいずれかの互変異性型又は構造異性型に限定されないことを示している。 The spiroindolone polyethylene glycol carbonate-based compound represented by the general formula I according to the present invention can exhibit tautomerism or structural isomerism. This is because the present invention comprises any tautomeric or structural isomer of these compounds, or a mixture thereof, and any tautomer or structural isomer represented by the above structural formula. It shows that it is not limited to.
本発明に係るスピロインドロンポリエチレングリコールカーボネート系化合物の薬学的に許容される塩とは、当該化合物と、適切な無毒性有機酸若しくは無毒性無機酸とからなる一般的な酸付加塩、又は当該化合物と、適切な無毒性有機塩基若しくは無毒性無機塩基とからなる一般的な塩基付加塩を意味する。前記無機酸として、塩酸、硫酸、リン酸、硝酸などが挙げられ、前記有機酸として、p−トルエンスルホン酸、サリチル酸、シュウ酸、クエン酸、乳酸、リンゴ酸等などが挙げられ、塩基付加塩の例として、アンモニウム塩、ナトリウム塩、カリウム塩及び第4級アンモニウム水酸化物が含まれる。 The pharmaceutically acceptable salt of the spiroindron polyethylene glycol carbonate-based compound according to the present invention is a general acid addition salt composed of the compound and an appropriate non-toxic organic acid or non-toxic inorganic acid, or the said. It means a general base addition salt consisting of a compound and a suitable non-toxic organic base or non-toxic inorganic base. Examples of the inorganic acid include hydrochloric acid, sulfuric acid, phosphoric acid, nitrate and the like, and examples of the organic acid include p-toluenesulfonic acid, salicylic acid, oxalic acid, citric acid, lactic acid, malic acid and the like, and base addition salts. Examples include ammonium salts, sodium salts, potassium salts and quaternary ammonium hydroxides.
本発明により提供されるスピロインドロンポリエチレングリコールカーボネート系化合物の製造方法は、下記の一般式IIIで表されるスピロインドロン系化合物と、下記の一般式IVで表される化合物とを、塩基の存在下で、求核置換反応させて、前記スピロインドロンポリエチレングリコールカーボネート系化合物を得るステップを含む。
(III)
(IV)
ここで、Y1、Y2、Y3、Y4、R1、R2、R3及びnは上記と同義である。
ここで、一般式IIIで表されるスピロインドロン系化合物は、WO2011/067185A1及びWO2011/134925A1に記載の方法を参照して調製することができる。
一般式IVで表される化合物は、例えば以下の反応により調製することができる。
In the method for producing a spiroindolone polyethylene glycol carbonate-based compound provided by the present invention, a spiroindolone-based compound represented by the following general formula III and a compound represented by the following general formula IV are based. In the presence, it comprises a step of subjecting to a nucleophilic substitution reaction to obtain the spiroindron polyethylene glycol carbonate-based compound.
(III)
(IV)
Here, Y 1 , Y 2 , Y 3 , Y 4 , R 1 , R 2 , R 3 and n are synonymous with the above.
Here, the spiroindolone-based compound represented by the general formula III can be prepared by referring to the methods described in WO2011 / 067185A1 and WO2011 / 134925A1.
The compound represented by the general formula IV can be prepared, for example, by the following reaction.
本発明により提供される抗腫瘍医薬組成物は、治療有効量の上記の一般式Iで表されるスピロインドロンポリエチレングリコールカーボネート系化合物、その立体異性体又はその薬学的に許容される塩及び薬学的に許容されるアジュバントを含む。 The antitumor pharmaceutical composition provided by the present invention is a therapeutically effective amount of a spiroindolone polyethylene glycol carbonate-based compound represented by the above general formula I, a stereoisomer thereof or a pharmaceutically acceptable salt thereof and a pharmacy. Includes a pharmaceutically acceptable adjuvant.
本発明の抗腫瘍医薬組成物は、必要に応じて、注射液、錠剤、カプセル剤及びその他の剤形とすることができる。前記薬学的に許容されるアジュバントは、抗腫瘍医薬組成物から調製される剤形に応じて、一般的なアジュバントから適切に選ぶことができる。例えば、注射用凍結乾燥品とする場合、前記薬学的に許容されるアジュバントは、賦形剤、希釈剤などを含むことができる。 The antitumor pharmaceutical composition of the present invention can be injectable solution, tablets, capsules and other dosage forms, if necessary. The pharmaceutically acceptable adjuvant can be appropriately selected from common adjuvants depending on the dosage form prepared from the antitumor pharmaceutical composition. For example, in the case of a lyophilized product for injection, the pharmaceutically acceptable adjuvant may include excipients, diluents and the like.
本発明によれば、癌治療薬の調製における一般式Iで表されるスピロインドロンポリエチレングリコールカーボネート系化合物、その立体異性体又はその薬学的に許容される塩の使用を提供する。 INDUSTRIAL APPLICABILITY The present invention provides the use of a spiroindolone polyethylene glycol carbonate-based compound represented by the general formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof in the preparation of a therapeutic agent for cancer.
本発明によれば、治療有効量の一般式Iで表されるスピロインドロンポリエチレングリコールカーボネート系化合物、その立体異性体又はその薬学的に許容される塩を癌患者に投与する癌の治療方法を提供する。 According to the present invention, a method for treating cancer in which a therapeutically effective amount of a spiroindron polyethylene glycol carbonate-based compound represented by the general formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered to a cancer patient. provide.
前記癌は、膀胱癌、乳癌、結腸癌、直腸癌、腎癌、肝癌、小細胞肺癌、非小細胞肺癌、食道癌、胆嚢癌、卵巣癌、膵臓腺癌、胃癌、子宮頸癌、甲状腺癌、前立腺癌、皮膚癌、急性リンパ性白血病、慢性骨髓性白血病、急性リンパ性白血病、B細胞リンパ腫、T細胞リンパ腫、ホジキンリンパ腫(Hodgkin’s lymphoma)、非ホジキンリンパ腫、有毛細胞リンパ腫、バーキットリンパ腫(Burkett’s lymphoma)、急性骨髓性白血病、黒色腫、子宮内膜癌、頭頚部癌、膠芽腫又は骨肉腫を含むが、これらに限定されない。 The cancers include bladder cancer, breast cancer, colon cancer, rectal cancer, renal cancer, liver cancer, small cell lung cancer, non-small cell lung cancer, esophageal cancer, bile sac cancer, ovarian cancer, pancreatic adenocarcinoma, gastric cancer, cervical cancer, and thyroid cancer. , Prostate cancer, skin cancer, acute lymphocytic leukemia, chronic osteoporosis leukemia, acute lymphocytic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, non-hodgkin's lymphoma, hair cell lymphoma, Berkit It includes, but is not limited to, lymphoma, acute osteoporosis, melanoma, endometrial cancer, head and neck cancer, glioblastoma or osteosarcoma.
本発明の化合物は、いずれの適切な常法で投与されてもよく、前記常法は、経口投与と、静脈内注射と、局所注射と、を含む。本発明の化合物の治療有効量とは、疾患の症状を予防、軽減又は改善するか、又は患者の生存期間を延長するために有効な量を意味する。 The compounds of the present invention may be administered by any suitable conventional method, which comprises oral administration, intravenous injection and local injection. The therapeutically effective amount of a compound of the present invention means an amount effective for preventing, alleviating or ameliorating the symptoms of a disease or prolonging the survival time of a patient.
本発明の化合物の治療有効量又は用量は、広い範囲で変化可能であり、且つ、当分野における既知の方法で決定される。上記の用量は、投与される具体的な化合物、投与経路、治療される疾患及び治療される患者を含む、各々の特定な状況の個体に応じて調整される。通常、体重約70kgの成人に経口又は非経口投与する場合、約10mg〜約10000mg、好ましくは約200mg〜約1000mgの1日用量が適切であるが、特に言及している場合、前記上限を超えてもよいと理解すべきである。1日用量は、単回投与又は分割投与として投与されるか、又は、非経口投与の場合には持続注入として投与される。 The therapeutically effective amounts or doses of the compounds of the invention are variable in a wide range and are determined by methods known in the art. The above doses are tailored to the individual in each particular situation, including the specific compound administered, the route of administration, the disease being treated and the patient being treated. Usually, when orally or parenterally administered to an adult weighing about 70 kg, a daily dose of about 10 mg to about 10000 mg, preferably about 200 mg to about 1000 mg is appropriate, but if otherwise specified, the above upper limit is exceeded. It should be understood that it is okay. The daily dose is administered as a single dose or in divided doses, or as a continuous infusion in the case of parenteral administration.
以下、本発明を実施例により具体的に説明するが、本発明の範囲はこれらの実施例に限定されるものではない。 Hereinafter, the present invention will be specifically described with reference to Examples, but the scope of the present invention is not limited to these Examples.
実施例1:中間体4−アミノ−3−メトキシ安息香酸メチルの合成
0℃で3−メトキシ安息香酸メチル(83.0g、500mmol)のH2SO4(70wt%、200ml)溶液にHNO3(65wt%、40ml)を滴下し、得られた混合物を終夜撹拌し、その後、氷水に注入した。このようにして得られた混合物を濾過し、得られた固形ケーキを水で洗浄し(3×300ml)、黄色の固体として4−ニトロ−3−メトキシ安息香酸メチル(84.4g、収率80%)を得た。
4−ニトロ−3−メトキシ安息香酸メチル(84.4g、400mmol)のエタノール(1500ml)溶液を、Pd/炭素(10%Pd、5.35g)触媒の存在下で、H2雰囲気中で5時間撹拌し、その後、この反応液をセライト(R)珪藻土により濾過して触媒を除去し、溶剤を真空下で蒸発させ、灰白色の固体を得て、この灰白色の固体をメタノールで再結晶し、4−アミノ−3−メトキシ安息香酸メチル(70.95g、392mmol、収率98%)を得た。
1H NMR(400MHz,CDCl3):δ7.55(dd,J=8.2Hz, 1.4Hz,1H),7.45(d,J=8.0Hz,1H),6.65(d,J=8.0Hz,1H),4.22(s,2H),3.90(s,3H),3.86(s,3H);
MS:C9H12NO3([M+H]+)計算値:182;実測値:182。
Example 1: Synthesis of intermediate 4-amino-3-methoxymethyl benzoate
HNO 3 (65 wt%, 40 ml) was added dropwise to a solution of methyl 3-methoxybenzoate (83.0 g, 500 mmol) in H 2 SO 4 (70 wt%, 200 ml) at 0 ° C., and the resulting mixture was stirred overnight. Then, it was injected into ice water. The mixture thus obtained was filtered and the resulting solid cake was washed with water (3 x 300 ml) and as a yellow solid methyl 4-nitro-3-methoxybenzoate (84.4 g, yield 80). %) Was obtained.
4-nitro-3-methoxybenzoate (84.4 g, 400 mmol) in ethanol (1500 ml) solution of, Pd / carbon (10% Pd, 5.35g) in the presence of a catalyst, 5 hours in a H 2 atmosphere After stirring, the reaction was filtered through Celite (R) diatomaceous soil to remove the catalyst, the solvent was evaporated under vacuum to give a grayish white solid, and the grayish white solid was recrystallized from methanol and 4 -Methyl amino-3-methoxybenzoate (70.95 g, 392 mmol, yield 98%) was obtained.
1 1 H NMR (400 MHz, CDCl 3 ): δ7.55 (dd, J = 8.2 Hz, 1.4 Hz, 1H), 7.45 (d, J = 8.0 Hz, 1H), 6.65 (d, J = 8.0Hz, 1H), 4.22 (s, 2H), 3.90 (s, 3H), 3.86 (s, 3H);
MS: C 9 H 12 NO 3 ([M + H] + ) Calculated value: 182; Measured value: 182.
実施例2:中間体4−(2−((t−ブトキシカルボニル)アミノ)アセチルアミノ)−3−メトキシ安息香酸メチルの合成
N2雰囲気中で、2−((t−ブトキシカルボニル)アミノ)酢酸(8.75g,50mmol)、Et3N(60mmol)の塩化メチレン(DCM)(150ml)と塩化アセチル(60mmol)の溶液を室温で1時間攪拌し、その後、4−アミノ−3−メトキシ安息香酸メチル(9.05g、50mmol)のエタノール(100ml)溶液を添加し、得られた混合物を終夜攪拌した。次いで、反応液に200mlの水を添加し、この反応混合物をDCMで抽出し(2×150ml)、有機層を合わせ、そして、水で洗浄し、Na2SO4により乾燥した後、溶剤を真空下で除去し、得られた残留物をシリカゲルカラムクロマトグラフィーにより精製し、白色の固体として目的化合物(12.0g、収率70%)を得た。
1H NMR(400MHz,CDCl3):δ8.59(s,1H),8.42(d, J=8.4Hz,1H),7.66(d,J=8.4Hz,1H),7.52(s,1 H),5.30(s,1H),3.96(d,J=5.2Hz,2H),3.91(s, 3H),3.89(s,3H),1.48(s,9H);
MS:C16H23N2O6([M+H]+)計算値:339;実測値:339.2。
Example 2: Synthesis of intermediate 4- (2-((t-butoxycarbonyl) amino) acetylamino) -3-methoxymethyl benzoate
In an N 2 atmosphere, 2 - ((t- butoxycarbonyl) amino) acetate (8.75 g, 50 mmol), a solution of methylene chloride (DCM) (150 ml) and acetyl chloride (60 mmol) of Et 3 N (60 mmol) The mixture was stirred at room temperature for 1 hour, then a solution of methyl 4-amino-3-methoxybenzoate (9.05 g, 50 mmol) in ethanol (100 ml) was added and the resulting mixture was stirred overnight. The reaction mixture was then added with 200 ml of water, the reaction mixture was extracted with DCM (2 x 150 ml), the organic layers were combined and washed with water, dried with Na 2 SO 4 , and then the solvent was vacuumed. The residue was removed below and the obtained residue was purified by silica gel column chromatography to obtain the target compound (12.0 g, 70% yield) as a white solid.
1 1 H NMR (400 MHz, CDCl 3 ): δ8.59 (s, 1H), 8.42 (d, J = 8.4 Hz, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7 .52 (s, 1H), 5.30 (s, 1H), 3.96 (d, J = 5.2Hz, 2H), 3.91 (s, 3H), 3.89 (s, 3H) , 1.48 (s, 9H);
MS: C 16 H 23 N 2 O 6 ([M + H] + ) Calculated value: 339; Measured value: 339.2.
実施例3:中間体4−(2−アミノアセチルアミノ)−3−メトキシ安息香酸メチル塩酸塩の合成
4−(2−((t‐ブトキシカルボニル)アミノ)アセチルアミノ)−3−メトキシ安息香酸メチル(11.83g、35 mmol)と濃塩酸(7.0ml)の酢酸エチル(100ml)溶液を室温で終夜攪拌し、その後、この反応液を濾過し、得られた濾過ケーキを酢酸エチル(2×50ml)で洗浄してから、乾燥し、白色の固体として4−(2−アミノアセチルアミノ)−3−メトキシ安息香酸メチル塩酸塩(6.562g、収率69%)を得た。
1H NMR(400MHz,DMSO):δ10.03(s,1H),8.49(s, 3H),8.20(d,J=8.4Hz,1H),7.57(d,J=8.4Hz,1 H),7.51(d,J=1.2Hz,1H),3.90(s,5H),3.83(s, 3H);
MS:C11H15N2O4([M−HCl+H]+)計算値:239;実測値:239。
Example 3: Synthesis of Intermediate 4- (2-Aminoacetylamino) -3-methoxymethyl benzoate hydrochloride
A solution of 4- (2-((t-butoxycarbonyl) amino) acetylamino) -3-methoxymethyl benzoate (11.83 g, 35 mmol) and concentrated hydrochloric acid (7.0 ml) in ethyl acetate (100 ml) at room temperature. Stir overnight, then filter the reaction, wash the resulting filtered cake with ethyl acetate (2 x 50 ml), then dry and as a white solid 4- (2-aminoacetylamino) -3. -Methyl benzoate hydrochloride (6.562 g, yield 69%) was obtained.
1 1 H NMR (400 MHz, DMSO): δ10.03 (s, 1H), 8.49 (s, 3H), 8.20 (d, J = 8.4 Hz, 1H), 7.57 (d, J = 8.4Hz, 1H), 7.51 (d, J = 1.2Hz, 1H), 3.90 (s, 5H), 3.83 (s, 3H);
MS: C 11 H 15 N 2 O 4 ([M-HCl + H] + ) Calculated value: 239; Measured value: 239.
実施例4:中間体(E)−4−(2−((3,3−ジメチルブチリデン)アミノ)アセチルアミノ)−3−メトキシ安息香酸メチルの合成
室温で4−(2−アミノアセチルアミノ)−3−メトキシ安息香酸メチル塩酸塩(6.56g、24mmol)のMTBE(メチル−t−ブチルエーテル)(100ml)懸濁液にトリエチルアミン(5ml)を添加し、1時間攪拌した後、3,3−ジメチル−n−ブチルアルデヒド(2.64g、26.4mmol)を滴下し、得られた混合物を室温で10時間攪拌した。その後、トリエチルアミン塩酸塩を除去するようにこの反応混合液を濾過し、そしてこの固形濾過ケーキをMTBEで洗浄し(3×30ml)、有機相を合わせ、有機溶剤を真空下で蒸発させ、粘調な油状物を得て、精製せずにそのまま次のステップに使用した。
Example 4: Synthesis of intermediate (E) -4- (2-((3,3-dimethylbutylidene) amino) acetylamino) -3-methoxymethyl benzoate
Triethylamine (5 ml) was added to a MTBE (methyl-t-butyl ether) (100 ml) suspension of 4- (2-aminoacetylamino) -3-methoxymethyl benzoate (6.56 g, 24 mmol) at room temperature. After stirring for 1 hour, 3,3-dimethyl-n-butylaldehyde (2.64 g, 26.4 mmol) was added dropwise, and the obtained mixture was stirred at room temperature for 10 hours. The reaction mixture is then filtered to remove triethylamine hydrochloride, and the solid filtered cake is washed with MTBE (3 x 30 ml), the organic phases are combined, the organic solvent is evaporated under vacuum and viscous. Oil was obtained and used as is in the next step without purification.
実施例5:中間体(E)−6−クロロ−3−(3−クロロ−2−フルオロベンジリデン)ジヒドロインドール−2−オンの合成
ピペリジン(1ml)の存在下で、6−クロロジヒドロインドール−2−オン(8.35g、50mmol)及び3−クロロ−2−フルオロベンズアルデヒド(8.295g、52.5mmol)を還流下で6時間撹拌し、その後、反応懸濁液を濾過し、得られた固体を収集してメタノールで洗浄し、そして乾燥し、生成物として黄色の固体の(E)−6−クロロ−3−(3−クロロ−2−フルオロベンジリデン)インドール−2−オン(14.63g、47.5mmol、収率95%)を得た。
1H NMR(400MHz,DMSO):δ10.85(s,1H),7.70(q, J=7.3Hz,2H),7.54(s,1H),7.36(t,J=8Hz,1H),7.16(d,J=8Hz,1H),6.92−6.86(m,2H);
MS:C15H9Cl2FNO([M+H]+)計算値:308;実測値:308.0。
Example 5: Synthesis of intermediate (E) -6-chloro-3- (3-chloro-2-fluorobenzylidene) dihydroindole-2-one
In the presence of piperidine (1 ml), 6-chlorodihydroindole-2-one (8.35 g, 50 mmol) and 3-chloro-2-fluorobenzaldehyde (8.295 g, 52.5 mmol) are stirred under reflux for 6 hours. The reaction suspension is then filtered, the resulting solid is collected, washed with methanol and dried, and the product is a yellow solid (E) -6-chloro-3- (3-chloro). -2-Fluorobenzylidene) indole-2-one (14.63 g, 47.5 mmol, 95% yield) was obtained.
1 1 H NMR (400 MHz, DMSO): δ10.85 (s, 1H), 7.70 (q, J = 7.3 Hz, 2H), 7.54 (s, 1H), 7.36 (t, J = 8Hz, 1H), 7.16 (d, J = 8Hz, 1H), 6.92-6.86 (m, 2H);
MS: C 15 H 9 Cl2 FNO ([M + H] + ) Calculated value: 308; Measured value: 308.0.
実施例6:中間体ラセミ−4−((2’S,3’R,4’S,5’R)−6−クロロ−4’−(3−クロロ−2−フルオロフェニル)−2’−ネオペンチル−2−オキソスピロ[ジヒドロインドール−3,3’−ピロリジン]−5’−カルボキサミド)−3−メトキシ安息香酸メチルの合成
1,8−ジアザビシクロウンデカ−7−エン(7ml)の存在下で、(E)−4−(2−((3,3−ジメチルブチリデン)アミノ)アセチルアミノ)−3−メトキシ安息香酸メチル(24mmol)と(E)−6−クロロ−3−(3−クロロ−2−フルオロベンジリデン)ジヒドロインドール−2−オン(24mmol)のトルエン(toluene)(60ml)溶液を終夜攪拌し、その後、100mlの水を添加し、得られた混合物を酢酸エチルで抽出し(2×150ml)、有機層を合わせ、そして、この有機層水で洗浄し、さらにNa2SO4により乾燥し、溶剤を真空下で除去し、得られた残留物をシリカゲルカラムクロマトグラフィーにより精製し、黄色の固体として目的化合物(13.9g、収率92%)を得た。
1H NMR(400MHz,CDCl3):δ10.65(s,1H),8.49 (d,J=8Hz,1H),7.94(s,1H),7.66(dd,J=8.6Hz, J=1Hz,1H),7.57(s,1H),7.51(t,J=6.8Hz,1H), 7.28(s,1H),7.16(t,J=7.4Hz,1H),7.07(dd,J =8.2Hz,J=1.4Hz,1H),6.92(t,J=8Hz,1H),6.73(d,J=1.2Hz,1H),4.69(t,J=8.8Hz,1H),4.44 (d,J=9.2Hz,1H),3.93(s,3H),3.90(s,3H),3.65(t,J=10.4Hz,1H),3.29(t,J=10.8Hz,1H),1.38−1.28(m,1H),0.96(s,9H),0.92(s,1H)(図1を参照);
MS:C32H33Cl2FN3O5([M+H]+)計算値:628;実測値:628.2。
Example 6: Intermediate Lasemi-4-((2'S, 3'R, 4'S, 5'R) -6-chloro-4'-(3-chloro-2-fluorophenyl) -2'- Synthesis of methyl neopentyl-2-oxospiro [dihydroindole-3,3'-pyrrolidin] -5'-carboxamide) -3-methoxymethyl benzoate
In the presence of 1,8-diazabicycloundec-7-ene (7 ml), (E) -4-(2-((3,3-dimethylbutylidene) amino) acetylamino) -3-methoxy benzo A solution of methyl (24 mmol) acid (24 mmol) and (E) -6-chloro-3- (3-chloro-2-fluorobenzylidene) dihydroindole-2-one (24 mmol) in toluene (60 ml) was stirred overnight, followed by , 100 ml of water was added, the resulting mixture was extracted with ethyl acetate (2 x 150 ml), the organic layers were combined and washed with this organic layer water, further dried with Na 2 SO4 and the solvent vacuumed. The residue was removed below and the resulting residue was purified by silica gel column chromatography to give the desired compound (13.9 g, 92% yield) as a yellow solid.
1 H NMR (400 MHz, CDCl 3 ): δ10.65 (s, 1H), 8.49 (d, J = 8 Hz, 1H), 7.94 (s, 1H), 7.66 (dd, J = 8) .6Hz, J = 1Hz, 1H), 7.57 (s, 1H), 7.51 (t, J = 6.8Hz, 1H), 7.28 (s, 1H), 7.16 (t, J) = 7.4Hz, 1H), 7.07 (dd, J = 8.2Hz, J = 1.4Hz, 1H), 6.92 (t, J = 8Hz, 1H), 6.73 (d, J = 1.2Hz, 1H), 4.69 (t, J = 8.8Hz, 1H), 4.44 (d, J = 9.2Hz, 1H), 3.93 (s, 3H), 3.90 ( s, 3H), 3.65 (t, J = 10.4Hz, 1H), 3.29 (t, J = 10.8Hz, 1H), 1.38-1.28 (m, 1H), 0. 96 (s, 9H), 0.92 (s, 1H) (see FIG. 1);
MS: C 32 H 33 Cl 2 FN 3 O 5 ([M + H] + ) Calculated value: 628; Measured value: 628.2.
実施例7:中間体1−クロロエチル(2−(2−メトキシエトキシ)エチル)カーボネートの合成
2−(2−メトキシエトキシ)エタノール(6.0g、50mmol)と1−クロロエチルカルボノクロリダート(1−chloroethyl carbonochloridate)(7.455g、52.5mmol)の溶液を、Et3N(4.04g、52.5mmol)の存在下で、室温で6時間攪拌し、その後、そこに200mlの水を添加し、この反応混合物をDCMで抽出し(2×150ml)、有機層を合わせ、そして、水で洗浄し、さらにNa2SO4により乾燥し、溶剤を真空下で除去し、得られた残留物をシリカゲルカラムクロマトグラフィーにより精製し、油状の目的化合物(8.475g、収率75%)を得た。
1H NMR(400MHz,CDCl3):δ6.41(q,J=5.7Hz,1 H),4.37−4.32(m,2H),3.73(t,J=4.8Hz,2H),3.66−3.62(m,2H),3.56−3.52(m,2H),3.37(s,3H), 1.81(d,J=6.4Hz,3H)。
Example 7: Synthesis of Intermediate 1-Chloroethyl (2- (2-methoxyethoxy) Ethyl) Carbonate
A solution of 2- (2-methoxyethoxy) ethanol (6.0 g, 50 mmol) and 1-chloroethyl carbonochlorodate (7.455 g, 52.5 mmol) was added to Et 3 N (4. In the presence of (04 g, 52.5 mmol), the mixture was stirred at room temperature for 6 hours, after which 200 ml of water was added, the reaction mixture was extracted with DCM (2 x 150 ml), the organic layers were combined and then The mixture was washed with water, further dried with Na 2 SO 4 , the solvent was removed under vacuum, and the obtained residue was purified by silica gel column chromatography to obtain an oily target compound (8.475 g, yield 75%). Got
1 1 H NMR (400 MHz, CDCl 3 ): δ6.41 (q, J = 5.7 Hz, 1 H), 4.37-4.32 (m, 2H), 3.73 (t, J = 4.8 Hz) , 2H), 3.66-3.62 (m, 2H), 3.56-3.52 (m, 2H), 3.37 (s, 3H), 1.81 (d, J = 6.4Hz) , 3H).
実施例8:ラセミ−9−オキソ−2,5,8,10−テトラオキサドデカン−11−イル−4−((2’S,3R,4’S,5’R)−6−クロロ−4’−(3−クロロ−2−フルオロフェニル)−2’−ネオペンチル−2−オキソスピロ[ジヒドロインドール−3,3’−ピロリジン]−5’−カルボキサミド)−3−メトキシ安息香酸エステル(ラセミ−SIP−PEG−2)の合成
ラセミ−4−((2’S,3’R,4’S,5’R)−6−クロロ−4’−(3−クロロ−2−フルオロフェニル)−2’−ネオペンチル−2−オキサスピロ[ジヒドロインドール−3,3’−ピロリジン]−5’−カルボキサミド)−3−メトキシ安息香酸メチル(13.816g、22mmol)のTHF(20ml)溶液にLiOH(5.8ml、H2O中50%濃度)を添加し、終夜攪拌し、その後、反応液を塩酸でpH=1に酸性化し、そして得られた反応混合物を酢酸エチルで抽出し(3×50ml)、有機層を合わせ、水で洗浄し、さらに無水Na2SO4により乾燥し、溶剤を真空下で除去し、得られた残留物をシリカゲルカラムクロマトグラフィーにより精製し、黄色の固体として対応する酸化合物(ラセミ−4−((2’S,3’R,4’S,5’R)−6−クロロ−4’−(3−クロロ−2−フルオロフェニル)−2’−ネオペンチル−2−オキソスピロ[ジヒドロインドール−3,3’−ピロリジン]−5’−カルボキサミド)−3−メトキシ安息香酸)(12.43g、収率92%)を得た。
ラセミ−4−((2’S,3’R,4’S,5’R)−6−クロロ−4’−(3−クロロ−2−フルオロフェニル)−2’−ネオペンチル−2−オキソスピロ[ジヒドロインドール−3,3’−ピロリジン]−5’−カルボキサミド)−3−メトキシ安息香酸(306mg、0.5mmol)と1−クロロエチル(2−(2−メトキシエトキシ)エチル)カーボネート(510mg、2.25mmol)のジメチルホルムアミド(10ml)溶液にNaOH(3mmol、975mg、6eq)を添加し、窒素ガス雰囲気中で終夜攪拌し、その後、10mlの水を添加し、この混合物を酢酸エチルで抽出し (2×15ml)、有機層を合わせ、水で洗浄し、さらに無水Na2SO4により乾燥し、溶剤を真空下で除去し、得られた残留物をシリカゲルカラムクロマトグラフィーにより精製し、黄色の固体として目的化合物(102mg、収率26%)を得た。
1H NMR(400MHz,CDCl3):δ10.62(s,1H),8.48 (d,J=8Hz,1H),7.79(d,J=1.6Hz,1H),7.66(dd, J=8.6Hz,1.4Hz,1H),7.56(s,1H),7.47(t,1H),7.33(d,J=8Hz,1H),7.23(d,J=9.2Hz,1H),7.19(d,J=7.6Hz,1H),7.07−6.98(m,2H),4.75−4.68(m,1H),4.50−4.42(m,2H),4.37−4.25(m,2H), 3.92(s,3H),3.82(t,2H),3.76−3.50(m,9H),2.18(bs,1H),1.65(d,J=5.2Hz,3H),1.36−1.22(m,1H),0.95(s,9H)(図2を参照)。
MS:C39H45Cl2FN3O10([M+H]+)計算値:804;実測値:804.2 。
Example 8: Racemic-9-oxo-2,5,8,10-tetraoxadodecane-11-yl-4-((2'S, 3R, 4'S, 5'R) -6-chloro-4 '-(3-Chloro-2-fluorophenyl) -2'-neopentyl-2-oxospiro [dihydroindole-3,3'-pyrrolidine] -5'-carboxamide) -3-methoxybenzoic acid ester (racemic-SIP-) Synthesis of PEG-2)
Racem-4-((2'S, 3'R, 4'S, 5'R) -6-chloro-4'-(3-chloro-2-fluorophenyl) -2'-neopentyl-2-oxaspiro [ dihydroindole-3,3'-pyrrolidin] -5'-carboxamido) -3-methoxybenzoate (13.816g, THF (20ml) was added LiOH (5.8ml, H 2 O in 50% strength 22 mmol) ) Is added and stirred overnight, after which the reaction solution is acidified to pH = 1 with hydrochloric acid, and the resulting reaction mixture is extracted with ethyl acetate (3 x 50 ml), the organic layers are combined and washed with water. , Further dried with anhydrous Na 2 SO 4 , the solvent was removed under vacuum and the resulting residue was purified by silica gel column chromatography to give the corresponding acid compound as a yellow solid (Racemi-4-((2'). S, 3'R, 4'S, 5'R) -6-chloro-4'-(3-chloro-2-fluorophenyl) -2'-neopentyl-2-oxospiro [dihydroindole-3,3'- Pyrrolidine] -5'-carboxamide) -3-methoxybenzoic acid) (12.43 g, yield 92%) was obtained.
Lacem-4-((2'S, 3'R, 4'S, 5'R) -6-chloro-4'-(3-chloro-2-fluorophenyl) -2'-neopentyl-2-oxospiro [ Dihydroindole-3,3'-pyrrolidin] -5'-carboxamide) -3-methoxybenzoic acid (306 mg, 0.5 mmol) and 1-chloroethyl (2- (2-methoxyethoxy) ethyl) carbonate (510 mg, 2. NaOH (3 mmol, 975 mg, 6 eq) was added to a 25 mmol) dimethylformamide (10 ml) solution, stirred overnight in a nitrogen gas atmosphere, then 10 ml of water was added and the mixture was extracted with ethyl acetate (2). × 15 ml), the organic layers were combined, washed with water, further dried with anhydrous Na 2 SO 4 , the solvent was removed under vacuum and the resulting residue was purified by silica gel column chromatography to give a yellow solid. The target compound (102 mg, yield 26%) was obtained.
1 1 H NMR (400 MHz, CDCl 3 ): δ10.62 (s, 1H), 8.48 (d, J = 8 Hz, 1H), 7.79 (d, J = 1.6 Hz, 1H), 7.66 (Dd, J = 8.6Hz, 1.4Hz, 1H), 7.56 (s, 1H), 7.47 (t, 1H), 7.33 (d, J = 8Hz, 1H), 7.23 (D, J = 9.2Hz, 1H), 7.19 (d, J = 7.6Hz, 1H), 7.07-6.98 (m, 2H), 4.75-4.68 (m, 1H), 4.50-4.42 (m, 2H), 4.37-4.25 (m, 2H), 3.92 (s, 3H), 3.82 (t, 2H), 3.76 -3.50 (m, 9H), 2.18 (bs, 1H), 1.65 (d, J = 5.2Hz, 3H), 1.36-1.22 (m, 1H), 0.95 (S, 9H) (see FIG. 2).
MS: C 39 H 45 Cl 2 FN 3 O 10 ([M + H] + ) Calculated value: 804; Measured value: 804.2.
実施例9:ラセミ−12−オキソ−2,5,8,11,13−ペンタオキサペンタデカン−14−イル−4−((2’S,3R,4’S,5’R)−6−クロロ−4’−(3−クロロ−2−フルオロフェニル)−2’−ネオペンチル−2−オキソスピロ[ジヒドロインドール−3,3’−ピロリジン]−5’−カルボキサミド)−3−メトキシ安息香酸エステル(ラセミ−SIP−PEG−3)の合成
ラセミ−4−((2’S,3’R,4’S,5’R)−6−クロロ−4’−(3−クロロ−2−フルオロフェニル)−2’−ネオペンチル−2−オキソスピロ[ジヒドロインドール−3,3’−ピロリジン]−5’−カルボキサミド)−3−メトキシ安息香酸(306mg、0.5mmol、実施例8の合成におけるステップ1を参照)と1−クロロエチル(2−(2−メトキシエトキシエトキシ)エチル)カーボネート(609mg、2.25mmol)のジメチルホルムアミド(10ml)溶液にNaOH(3mmol、975mg、6eq)を添加し、窒素ガス雰囲気中で終夜攪拌し、その後、10mlの水を添加し、この混合物を酢酸エチル(EA)で抽出し(2×15ml)、有機層を合わせ、水で洗浄し、さらに無水Na2SO4により乾燥し、溶剤を真空下で除去し、得られた残留物をシリカゲルカラムクロマトグラフィーにより精製し、白色の固体として目的化合物(100mg、収率24%)を得た。
1H NMR(CDCl3、400MHz):δ10.62(s,1H),8.50(d,J=4.2Hz,1H),7.79(d,J=0.6Hz,1H),7.74(d,J=4.2Hz,1H),7.61(s,1H),7.47(t,J=6.4Hz,1 H),7.33(d,J=7.6Hz,1H),7.10−7.25(m,2H),7.02(t,J=7.8Hz,1H),4.70(d,J=4.8Hz,1H),4.40−4.50(m,3H),3.93(s,3H),3.78−3.80(m,2H), 3.72(d,J=9.0Hz,4H),3.64(s,9H),3.50−3.54(m,2H),3.36(s,3H),1.23−1.35(m,1H),0.95(s, 9H),0.90(s,1H);
MS:C41H49Cl2FN3O11([M+H]+)計算値:848;実測値:848.3。
Example 9: Racemic-12-oxo-2,5,8,11,13-pentaoxapentadecane-14-yl-4-((2'S, 3R, 4'S, 5'R) -6-chloro -4'-(3-Chloro-2-fluorophenyl) -2'-neopentyl-2-oxospiro [dihydroindole-3,3'-pyrrolidine] -5'-carboxamide) -3-methoxybenzoic acid ester (racemic-) Synthesis of SIP-PEG-3)
Racem-4-((2'S, 3'R, 4'S, 5'R) -6-chloro-4'-(3-chloro-2-fluorophenyl) -2'-neopentyl-2-oxospiro [ Dihydroindole-3,3'-pyrrolidin] -5'-carboxamide) -3-methoxybenzoic acid (306 mg, 0.5 mmol, see
1 1 H NMR (CDCl 3 , 400 MHz): δ10.62 (s, 1H), 8.50 (d, J = 4.2 Hz, 1H), 7.79 (d, J = 0.6 Hz, 1H), 7 .74 (d, J = 4.2Hz, 1H), 7.61 (s, 1H), 7.47 (t, J = 6.4Hz, 1H), 7.33 (d, J = 7.6Hz) , 1H), 7.10-7.25 (m, 2H), 7.02 (t, J = 7.8Hz, 1H), 4.70 (d, J = 4.8Hz, 1H), 4.40 -4.50 (m, 3H), 3.93 (s, 3H), 3.78-3.80 (m, 2H), 3.72 (d, J = 9.0Hz, 4H), 3.64 (S, 9H), 3.50-3.54 (m, 2H), 3.36 (s, 3H), 1.23-1.35 (m, 1H), 0.95 (s, 9H), 0.90 (s, 1H);
MS: C 41 H 49 Cl 2 FN 3 O 11 ([M + H] + ) Calculated value: 848; Measured value: 848.3.
実施例10:下記の構造式で表される化合物(4−((2’S,3’R,4’S,5’R)−6−クロロ−4’−(3−クロロ−2−フルオロフェニル)−2’−ネオペンチル−2−オキソスピロ[ジヒドロインドール−3,3’−ピロリジン]−5’−カルボキサミド)−3−メトキシ安息香酸−(R)−N,N−ジメチル−1−フェニル−1−エチルアミン塩、R−アミン塩)の合成
ラセミ−4−((2’S,3’R,4’S,5’R)−6−クロロ−4’−(3−クロロ−2−フルオロフェニル)−2’−ネオペンチル−2−オキソスピロ[ジヒドロインドール−3,3’−ピロリジン]−5’−カルボキサミド)−3−メトキシ安息香酸(4.0g、6.5mmol、実施例8の合成にかけるステップ1を参照)と(R)−N,N−ジメチル−1−フェニル−1−エチルアミン(1.12g、7.49mmol、(R)−N,N−dimethyl−1−phenylethan−1−amine)との混合物を酢酸エチルに分散させ、60℃に加熱してこの温度で2時間撹拌し、その後、常温まで冷却して終夜攪拌した。析出した固体を濾過して低温酢酸エチルで洗浄し、乾燥後、白色の固体としてR−アミン塩4−((2’S,3’R,4’S,5’R)−6−クロロ−4’−(3−クロロ−2−フルオロフェニル)−2’−ネオペンチル−2−オキソスピロ[ジヒドロインドール−3,3’−ピロリジン]−5’−カルボキサミド)−3−メトキシ安息香酸−(R)−N,N−ジメチル−1−フェニル−1−エチルアミン塩(2.0g)を得た。
1H NMR(d6−DMSO,400MHz):δ10.75(s,1H),10.47(s,1H),8.38(d,J=8.4Hz,1H),7.70(d,J=8.0Hz,1H),7.61(t,J=7.0Hz,1H),7.55−7.58(m,2H),7.37(t,J=7.4Hz,1H),7.25−7.33(m,4H),7.22(t,J=6.8Hz,1H),7.17(t,J=8.0Hz,1H),7.00(d,J=8.4Hz,1H),6.67(s,1H),4.67(t,J=7.6Hz,1H),4.47(d,J=9.6Hz,1H),3.90(s,3H),3.65−3.90(m,1H),3.20−3.40(m,2H),2.08(s,6H),1.29−1.32(m,1H),1.26(d,J=6.8Hz,3H),0.91 (s,9H),0.76(d,J=14Hz,1H)(図3を参照)。
Example 10: A compound represented by the following structural formula (4-((2'S, 3'R, 4'S, 5'R) -6-chloro-4'-(3-chloro-2-fluoro) Phenyl) -2'-neopentyl-2-oxospiro [dihydroindole-3,3'-pyrrolidine] -5'-carboxamide) -3-methoxybenzoic acid- (R) -N, N-dimethyl-1-phenyl-1 -Synthesis of ethylamine salt, R-amine salt)
Racem-4-((2'S, 3'R, 4'S, 5'R) -6-chloro-4'-(3-chloro-2-fluorophenyl) -2'-neopentyl-2-oxospiro [ Dihydroindole-3,3'-pyrrolidin] -5'-carboxamide) -3-methoxybenzoic acid (4.0 g, 6.5 mmol, see
1 H NMR (d 6- DMSO, 400 MHz): δ10.75 (s, 1H), 10.47 (s, 1H), 8.38 (d, J = 8.4 Hz, 1H), 7.70 (d) , J = 8.0Hz, 1H), 7.61 (t, J = 7.0Hz, 1H), 7.55-7.58 (m, 2H), 7.37 (t, J = 7.4Hz, 1H), 7.25-7.33 (m, 4H), 7.22 (t, J = 6.8Hz, 1H), 7.17 (t, J = 8.0Hz, 1H), 7.00 ( d, J = 8.4Hz, 1H), 6.67 (s, 1H), 4.67 (t, J = 7.6Hz, 1H), 4.47 (d, J = 9.6Hz, 1H), 3.90 (s, 3H), 3.65-3.90 (m, 1H), 3.20-3.40 (m, 2H), 2.08 (s, 6H), 1.29-1. 32 (m, 1H), 1.26 (d, J = 6.8Hz, 3H), 0.91 (s, 9H), 0.76 (d, J = 14Hz, 1H) (see FIG. 3).
実施例11:キラル−12−オキソ−2,5,8,11,13−ペンタオキサペンタデカン−14−イル−4−((2’S,3R,4’S,5’R)−6−クロロ−4’−(3−クロロ−2−フルオロフェニル)−2’−ネオペンチル−2−オキソスピロ[ジヒドロインドール−3,3’−ピロリジン]−5’−カルボキサミド)−3−メトキシ安息香酸エステル(キラル−R−SIP−PEG−3)の合成
4−((2’S,3’R,4’S,5’R)−6−クロロ−4’−(3−クロロ−2−フルオロフェニル)−2’−ネオペンチル−2−オキソスピロ[ジヒドロインドール−3,3’−ピロリジン]−5’−カルボキサミド)−3−メトキシ安息香酸−(R)−N,N−ジメチル−1−フェニル−1−エチルアミン塩(382mg、0.5mmol)と1−クロロエチル(2−(2−メトキシエトキシエトキシ)エチル)カーボネート(609mg、2.25mmol)のジメチルホルムアミド(10ml)溶液に、NaOH(3mmol、975mg、6eq)を添加し、窒素ガス雰囲気中で終夜攪拌し、その後、10mlの水を添加し、この混合物を酢酸エチルで抽出し(2×15ml)、有機層を合わせ、水で洗浄し、さらに無水Na2SO4により乾燥し、溶剤を真空下で除去し、得られた残留物をシリカゲルカラムクロマトグラフィーにより精製し、白色の固体として目的化合物(98mg、収率23%)を得た。[α]20 D=−138o(0.1g/100ml、CH3OH)。
1H NMR(CDCl3、400MHz):δ10.62(s,1H),8.51(d,J=8.8Hz,1H),7.92(s,1H),7.73(d,J=8.4Hz,1H),7.60(s,1H),7.47(t,J=6.8Hz,1H),7.33(d,J=7.6Hz,1H),7.10−7.25(m,2H),7.02(t,J=7.8Hz,1H),4.68−4.80(m,1H),4.40−4.50(m,3H),3.93(s,3H),3.80−3.88(m,2H),3.70−3.80(m,4H),3.60−3.70(m,9H),3.50−3.58(m,2H),3.36(s,3H),1.23−1.35(m,1H),0.95(s,9H),0.85−0.90(m,1H)(図4を参照);
MS:C41H49Cl2FN3O11([M+H]+)計算値:848;実測値:848.3。
Example 11: Chiral-12-oxo-2,5,8,11,13-pentaoxapentadecane-14-yl-4-((2'S, 3R, 4'S, 5'R) -6-chloro -4'-(3-Chloro-2-fluorophenyl) -2'-neopentyl-2-oxospiro [dihydroindole-3,3'-pyrrolidin] -5'-carboxamide) -3-methoxybenzoic acid ester (chiral-) Synthesis of R-SIP-PEG-3)
4-((2'S, 3'R, 4'S, 5'R) -6-chloro-4'-(3-chloro-2-fluorophenyl) -2'-neopentyl-2-oxospiro [dihydroindole] -3,3'-pyrrolidin] -5'-carboxamide) -3-methoxybenzoic acid- (R) -N, N-dimethyl-1-phenyl-1-ethylamine salt (382 mg, 0.5 mmol) and 1-chloroethyl NaOH (3 mmol, 975 mg, 6 eq) was added to a solution of (2- (2-methoxyethoxyethoxy) ethyl) carbonate (609 mg, 2.25 mmol) in dimethylformamide (10 ml), and the mixture was stirred overnight in a nitrogen gas atmosphere. Then 10 ml of water was added, the mixture was extracted with ethyl acetate (2 x 15 ml), the organic layers were combined, washed with water and further dried with anhydrous Na 2 SO 4 to remove the solvent under vacuum. The obtained residue was purified by silica gel column chromatography to obtain the target compound (98 mg, 23% yield) as a white solid. [Α] 20 D = -138 o (0.1 g / 100 ml, CH 3 OH).
1 1 H NMR (CDCl 3 , 400 MHz): δ10.62 (s, 1H), 8.51 (d, J = 8.8 Hz, 1H), 7.92 (s, 1H), 7.73 (d, J) = 8.4Hz, 1H), 7.60 (s, 1H), 7.47 (t, J = 6.8Hz, 1H), 7.33 (d, J = 7.6Hz, 1H), 7.10 -7.25 (m, 2H), 7.02 (t, J = 7.8Hz, 1H), 4.68-4.80 (m, 1H), 4.40-4.50 (m, 3H) , 3.93 (s, 3H), 3.80-3.88 (m, 2H), 3.70-3.80 (m, 4H), 3.60-3.70 (m, 9H), 3 .50-3.58 (m, 2H), 3.36 (s, 3H), 1.23-1.35 (m, 1H), 0.95 (s, 9H), 0.85-0.90 (M, 1H) (see FIG. 4);
MS: C 41 H 49 Cl 2 FN 3 O 11 ([M + H] + ) Calculated value: 848; Measured value: 848.3.
実施例12:ラセミ−24−オキソ−2,5,8,11,14,17,20,23,25−ノナオキサヘプタコサン−26−イル−4−((2’S,3R,4’S,5’R)−6−クロロ−4’−(3−クロロ−2−フルオロフェニル)−2’−ネオペンチル−2−オキソスピロ[ジヒドロインドール−3,3’−ピロリジン]−5’−カルボキサミド)−3−メトキシ安息香酸エステル(ラセミ−SIP−PEG−7)の合成
ラセミ−4−((2’S,3’R,4’S,5’R)−6−クロロ−4’−(3−クロロ−2−フルオロフェニル)−2’−ネオペンチル−2−オキソスピロ[ジヒドロインドール−3,3’−ピロリジン]−5’−カルボキサミド)−3−メトキシ安息香酸(306mg、0.5mmol)と1−クロロエチル(2,5,8,11,14,17,20−ヘプタオキサドコサン−22−イル)カーボネート(1−chloroethyl(2,5,8,11,14,17,20−heptaoxadocosan−22−yl)carbonate)(1.00g、2.25mmol)のジメチルホルムアミド(10ml)溶液に、NaOH(3mmol、975mg、6eq)を添加し、窒素ガス雰囲気中で終夜攪拌し、その後、10mlの水を添加し、この混合物を酢酸エチルで抽出し(2×15ml)、有機層を合わせ、水で洗浄し、さらに無水Na2SO4により乾燥し、溶剤を真空下で除去し、得られた残留物をシリカゲルカラムクロマトグラフィーにより精製し、目的化合物(77 mg、収率15%)を得た。
計算分子式(M+H):C49H65Cl2FN3O15;計算分子量:1024.3777;測定値HRMS(C49H65Cl2FN3O15):1024.3772。
Example 12: Racemic-24-oxo-2,5,8,11,14,17,20,23,25-Nonaoxaheptacosan-26-yl-4-((2'S, 3R, 4'S) , 5'R) -6-chloro-4'-(3-chloro-2-fluorophenyl) -2'-neopentyl-2-oxospiro [dihydroindole-3,3'-pyrrolidine] -5'-carboxamide)- Synthesis of 3-methoxybenzoic acid ester (racemic-SIP-PEG-7)
Racem-4-((2'S, 3'R, 4'S, 5'R) -6-chloro-4'-(3-chloro-2-fluorophenyl) -2'-neopentyl-2-oxospiro [ Dihydroindole-3,3'-pyrrolidin] -5'-carboxamide) -3-methoxybenzoic acid (306 mg, 0.5 mmol) and 1-chloroethyl (2,5,8,11,14,17,20-heptaoxa) Docosan-22-yl) carbonate (1-chromoethyl (2,5,8,11,14,17,20-heptaoxadocosan-22-yl) solvent) (1.00 g, 2.25 mmol) dimethylformamide (10 ml) To the solution, NaOH (3 mmol, 975 mg, 6 eq) was added and stirred overnight in a nitrogen gas atmosphere, then 10 ml of water was added and the mixture was extracted with ethyl acetate (2 x 15 ml) to remove the organic layer. The mixture was combined, washed with water, further dried with anhydrous Na 2 SO 4 , the solvent was removed under vacuum, and the obtained residue was purified by silica gel column chromatography to obtain the target compound (77 mg, yield 15%). Got
Calculated molecular formula (M + H): C 49 H 65 Cl 2 FN 3 O 15 ; Calculated molecular weight: 1024.3777; Measured value HRMS (C 49 H 65 Cl 2 FN 3 O 15 ): 1024.3772.
実施例13:ラセミ−4−((2’S,3’R,4’S,5’R)−6−クロロ−4’−(3−クロロ−2−フルオロフェニル)−2’−ネオペンチル−2−オキソスピロ[ジヒドロインドール−3,3’−ピロリジン]−5’−カルボキサミド)−3−メトキシ安息香酸メトキシポリエチレングリコール1000カーボネート(ラセミ−SIP−MPEG−1000)の合成
メトキシポリエチレングリコール1000[MPEG−1000(CAS:9004−74−4、平均分子量Mn=1000、TCI)、1.0g、1.0mmol]及びトリエチルアミン(505mg、5.0mmol)を塩化メチレン(10ml)に溶解し、氷浴条件でこの溶液に1−クロロエチルカルボノクロリダート(715mg、5.0mmol)を滴下し、生成した混合物を24時間攪拌反応させ、水洗、抽出、乾燥後、1−クロロエチルメトキシポリエチレングリコール1000カーボネートを得て、そのまま次の反応に使用した。
ラセミ−4−((2’S,3’R,4’S,5’R)−6−クロロ−4’−(3−クロロ−2−フルオロフェニル)−2’−ネオペンチル−2−オキソスピロ[ジヒドロインドール−3,3’−ピロリジン]−5’−カルボキサミド)−3−メトキシ安息香酸(306mg、0.5mmol)と1−クロロエチルメトキシポリエチレングリコール1000カーボネート(2.53g、2.25mmol)のジメチルホルムアミド(10ml)溶液に、NaOH(3mmol、975mg、6eq)を添加し、窒素ガス雰囲気中で終夜攪拌し、その後、10mlの水を添加し、この混合物を酢酸エチルで抽出し(2×15ml)、有機層を合わせ、水で洗浄し、さらに無水Na2SO4により乾燥し、溶剤を真空下で除去し、得られた残留物を分取液体クロマトグラフィーにより精製し、目的化合物(128mg、収率15%)を得た。MALDI−TOF−MS:約1700(図5を参照)。
Example 13: Racemic-4-((2'S, 3'R, 4'S, 5'R) -6-chloro-4'-(3-chloro-2-fluorophenyl) -2'-neopentyl- Synthesis of 2-oxospiro [dihydroindole-3,3'-pyrrolidin] -5'-carboxamide) -3-methoxybenzoate methoxypolyethylene glycol 1000 carbonate (racemic-SIP-MPEG-1000)
Methylene chloride (10 ml) with methoxypolyethylene glycol 1000 [MPEG-1000 (CAS: 9004-74-4, average molecular weight Mn = 1000, TCI), 1.0 g, 1.0 mmol] and triethylamine (505 mg, 5.0 mmol) After dissolution, 1-chloroethyl carbonochloridate (715 mg, 5.0 mmol) was added dropwise to this solution under ice bath conditions, and the resulting mixture was stirred and reacted for 24 hours, washed with water, extracted, dried, and then 1-chloroethyl. A methoxypolyethylene glycol 1000 carbonate was obtained and used as it was in the next reaction.
Racem-4-((2'S, 3'R, 4'S, 5'R) -6-chloro-4'-(3-chloro-2-fluorophenyl) -2'-neopentyl-2-oxospiro [ Dihydroindole-3,3'-pyrrolidin] -5'-carboxamide) -3-methoxybenzoic acid (306 mg, 0.5 mmol) and 1-chloroethylmethoxypolyethylene glycol 1000 carbonate (2.53 g, 2.25 mmol) dimethyl To a solution of formamide (10 ml), NaOH (3 mmol, 975 mg, 6 eq) was added and stirred overnight in a nitrogen gas atmosphere, then 10 ml of water was added and the mixture was extracted with ethyl acetate (2 x 15 ml). , The organic layers are combined, washed with water, further dried with anhydrous Na 2 SO 4 , the solvent is removed under vacuum and the resulting residue is purified by preparative liquid chromatography to obtain the compound of interest (128 mg, yield).
実施例14:ラセミ−4−((2’S,3’R,4’S,5’R)−6−クロロ−4’−(3−クロロ−2−フルオロフェニル)−2’−ネオペンチル−2−オキソスピロ[ジヒドロインドール−3,3’−ピロリジン]−5’−カルボキサミド)−3−メトキシ安息香酸メトキシポリエチレングリコール2000カーボネート(ラセミ−SIP−MPEG−2000)の合成
1−クロロエチルメトキシポリエチレングリコール2000カーボネートは、実施例13にかける1−クロロエチルメトキシポリエチレングリコール1000カーボネートの合成方法を参照して原料であるメトキシポリエチレングリコール2000(CAS:9004−74−4、平均分子量Mn=2000、Sigma−Aldrich)から調製することができる。
ラセミ−4−((2’S,3’R,4’S,5’R)−6−クロロ−4’−(3−クロロ−2−フルオロフェニル)−2’−ネオペンチル−2−オキサスピロ[ジヒドロインドール−3,3’−ピロリジン]−5’−カルボキサミド)−3−メトキシ安息香酸(306mg、0.5mmol)と1−クロロエチルメトキシポリエチレングリコール2000カーボネート(4.80g、2.25mmol)のジメチルホルムアミド(10ml)溶液に、NaOH(3mmol、975mg、6eq)を添加し、窒素ガス雰囲気中で終夜攪拌し、その後、10mlの水を添加し、この混合物を酢酸エチルで抽出し(2×15ml)、有機層を合わせ、水で洗浄し、さらに無水Na2SO4により乾燥し、溶剤を真空下で除去し、得られた残留物を分取液体クロマトグラフィーにより精製し、目的化合物(220mg、収率17%)を得た。MALDI−TOF−MS:約2600(図6を参照)。
Example 14: Racemic-4-((2'S, 3'R, 4'S, 5'R) -6-chloro-4'-(3-chloro-2-fluorophenyl) -2'-neopentyl- Synthesis of 2-oxospiro [dihydroindole-3,3'-pyrrolidin] -5'-carboxamide) -3-
1-
Racem-4-((2'S, 3'R, 4'S, 5'R) -6-chloro-4'-(3-chloro-2-fluorophenyl) -2'-neopentyl-2-oxaspiro [ Dihydroindole-3,3'-pyrrolidin] -5'-carboxamide) -3-methoxybenzoic acid (306 mg, 0.5 mmol) and 1-
実施例15−17:以下の構造式で表されるラセミ化合物の合成
(合成経路について実施例8を参照する)
実施例15:
質量分析計による計算値(M+H)+:790
質量分析計による測定値(M+H)+:790.2
実施例16:
質量分析計による計算値(M+H)+:818
質量分析計による測定値(M+H)+:818.3
実施例17:
質量分析計による計算値(M+H)+:860
質量分析計による測定値(M+H)+:860.4
Example 15-17: Synthesis of racemic compound represented by the following structural formula (see Example 8 for the synthetic route)
Example 15:
Calculated by mass spectrometer (M + H) + : 790
Measured value by mass spectrometer (M + H) + : 790.2
Example 16:
Calculated by mass spectrometer (M + H) + : 818
Measured value by mass spectrometer (M + H) + : 818.3
Example 17:
Calculated by mass spectrometer (M + H) + : 860
Measured value by mass spectrometer (M + H) + : 860.4
実施例18〜20:如下の構造式で表されるラセミ化合物の合成
(合成経路について実施例9、12を参照する)
実施例18:
質量分析計による計算値(M+H)+:790
質量分析計による測定値(M+H)+:790.3
実施例19:
質量分析計による計算値(M+H)+:804
質量分析計による測定値(M+H)+:804.3
実施例20:
質量分析計による計算値(M+H)+:1006
質量分析計による測定値(M+H)+:1006.4
Examples 18 to 20: Synthesis of racemic compounds represented by the following structural formulas (see Examples 9 and 12 for synthetic pathways)
Example 18:
Calculated by mass spectrometer (M + H) + : 790
Measured value by mass spectrometer (M + H) + : 790.3
Example 19:
Calculated value by mass spectrometer (M + H) + : 804
Measured value by mass spectrometer (M + H) + : 804.3
Example 20:
Calculated by mass spectrometer (M + H) + : 1006
Measured value by mass spectrometer (M + H) + : 1006.4
試験実施例
本発明の化合物の水溶性に対する改善作用
1、実験目的
本発明の化合物のポリエチレングリコールカーボネート構造によるスピロインドロン系化合物の水溶性に対する改善作用を調べる。
2、実験方法
30.00mgの標準品であるラセミ−SIP(ラセミ−spiroindolinone pyrrolidinecarboxamide;Org.Process Res.Dev.2013;17(2):247−256)を正確に秤量し、10mlのメスフラスコに入れ、アセトニトリルを加えて溶解させ、そして液面を目盛りに合わせ、3.00mg/mlのラセミ−SIP母液になるように調製し、低温、遮光で保存して準備した。
クロマトグラフィー条件:Iinertsil ODS−3 カラム(4.6mm×150mm、5μm);移動相:アセトニトリル−20%リン酸溶液(40:60、V/V);流速:1ml/min;検出波長:286nm;注入量:20μl;温度:室温。このクロマトグラフィー条件下で、濃度が適切なラセミ−SIP標準品溶液を注入して測定したところ、ラセミ−SIPピークの保持時間が4.5minであり、その不純物が主ピークの測定に干渉しなかった。
ラセミ−SIP標準品の母液を正確に秤量し、10mlのメスフラスコに入れ、液面を目盛りに合わせるようにアセトニトリルを加えて希釈し、良く振って濃度がそれぞれ0.1、0.5、1.0、2.0及び3.0μg/mlの一連の標準溶液を得た。前記クロマトグラフィー条件で検出し、ピーク面積を記録し、ピーク面積(Y)を濃度(X)に対してプロットし、回帰分析し、回帰方程式(Y=88.85X+0.2221、r2=0.9998)を得て、この式に基づいてサンプルの濃度を計算した。
過剰なラセミ−SIP、ラセミ−4−((2’S,3’R,4’S,5’R)−6−クロロ−4’−(3−クロロ−2−フルオロフェニル)−2’−ネオペンチル−2−オキソスピロ[ジヒドロインドール−3,3’−ピロリジン]−5’−カルボキサミド)−3−メトキシ安息香酸(ラセミ−SIP−酸)(実施例8における反応を参照すると、ラセミ−SIP−PEG−2の前駆体である)、ラセミ−SIP−PEG−2(即ち、実施例8の化合物)、ラセミ−SIP−PEG−3(即ち、実施例9の化合物)、キラル−R−SIP−PEG−3(即ち、実施例11の化合物)、ラセミ−SIP−PEG−7(即ち、実施例12の化合物)、ラセミ−SIP−MPEG−1000(即ち、実施例13的化合物)、ラセミ−SIP−MPEG−2000(即ち、実施例14の化合物)をそれぞれ栓付試験管に入れ、適量の水を加え、溶解が進行しなくなるまで超音波処理し、振盪器に入れ(100 r/min)、(25±1)℃で24h振盪し、溶液が平衡に到達した後、各化合物の飽和溶液を取り出し、遠心機に置いて、10000 r/minで10min遠心し、上澄み液を正確に吸い取り、アセトニトリルで定量的に希釈してから、サンプルを注入して測定し、SIP検量線から異なる誘導体の水への溶解度を近似的に計算した。
3、実験結果
溶解度試験の結果から、ラセミ−SIP及びラセミ−SIP−酸は、水への溶解度が極めて低く(<0.1mg/ml)、ほとんど溶解しないが、ラセミ−SIP−PEG−2(即ち、実施例8の化合物)の溶解度>0.4mg/mlで、ラセミ−SIP−PEG−3(即ち、実施例9の化合物)の溶解度>3mg/mlで、キラル−R−SIP−PEG−3(即ち、実施例11の化合物)の溶解度>8mg/mlで、ラセミ−SIP−PEG−7(即ち、実施例12の化合物)の溶解度が30mg/mlで、ラセミ−SIP−MPEG−1000(即ち、実施例13的化合物)の溶解度>100mg/mlで、ラセミ−SIP−MPEG−2000(即ち、実施例14の化合物)の溶解度>100mg/mlであることが示された。PEG(即ち、−CH2−CH2−O−)鎖長が増加するにつれて、溶解性がより良くなるとの結論が得られた。
Test Examples Improvement effect on water solubility of the compound of the
2. Experimental method Weigh accurately 30.00 mg of the standard racemic-SIP (racemic-spirolinone pyrolidine carboxamide; Org. Acetonitrile Res. Dev. 2013; 17 (2): 247-256) into a 10 ml volumetric flask. It was added, and acetonitrile was added to dissolve it, and the liquid level was adjusted to the scale to prepare a racemic-SIP mother liquor of 3.00 mg / ml, which was stored at low temperature and in the dark.
Chromatographic conditions: Room temperature ODS-3 column (4.6 mm × 150 mm, 5 μm); Mobile phase: Acetonitrile-20% phosphate solution (40:60, V / V); Flow velocity: 1 ml / min; Detection wavelength: 286 nm; Injection volume: 20 μl; Temperature: Room temperature. When measured by injecting a racemic-SIP standard solution having an appropriate concentration under these chromatographic conditions, the retention time of the racemic-SIP peak was 4.5 min, and the impurities did not interfere with the measurement of the main peak. It was.
Accurately weigh the mother liquor of the Lasemi-SIP standard product, put it in a 10 ml volumetric flask, add acetonitrile to dilute it so that the liquid level is aligned with the scale, and shake well to make the concentrations 0.1, 0.5, 1 respectively. A series of standard solutions of 0.0, 2.0 and 3.0 μg / ml were obtained. Detected under the above chromatographic conditions, the peak area is recorded, the peak area (Y) is plotted against the concentration (X), regression analysis is performed, and the regression equation (Y = 88.85X + 0.2221, r 2 = 0. 9998) was obtained, and the concentration of the sample was calculated based on this equation.
Excess Racemic-SIP, Racemic-4-((2'S, 3'R, 4'S, 5'R) -6-Chloro-4'-(3-Chloro-2-fluorophenyl) -2'- Neopentyl-2-oxospiro [dihydroindole-3,3'-pyrrolidin] -5'-carboxamide) -3-methoxybenzoic acid (racemic-SIP-acid) (referring to the reaction in Example 8) racemic-SIP-PEG -2 precursor), racemic-SIP-PEG-2 (ie, compound of Example 8), racemic-SIP-PEG-3 (ie, compound of Example 9), chiral-R-SIP-PEG -3 (ie, the compound of Example 11), Racemic-SIP-PEG-7 (ie, the compound of Example 12), Racemic-SIP-PEG-1000 (ie, the compound of Example 13), Racemic-SIP- Each of MPEG-2000 (that is, the compound of Example 14) was placed in a stoppered test tube, an appropriate amount of water was added, ultrasonic treatment was performed until dissolution did not proceed, and the mixture was placed in a shaker (100 r / min). Shake at 25 ± 1) ° C. for 24 hours, after the solution reaches equilibrium, remove the saturated solution of each compound, place in a centrifuge, centrifuge at 10000 r / min for 10 min, accurately absorb the supernatant and with acetonitrile. After quantitatively diluting, the sample was injected and measured, and the solubility of different derivatives in water was approximately calculated from the SIP calibration line.
3. Experimental results From the results of the solubility test, racemic-SIP and racemic-SIP-acid have extremely low solubility in water (<0.1 mg / ml) and are hardly soluble, but racemic-SIP-PEG-2 ( That is, the solubility of (compound of Example 8)> 0.4 mg / ml and the solubility of racemic-SIP-PEG-3 (ie, the compound of Example 9)> 3 mg / ml, chiral-R-SIP-PEG- 3 (ie, the compound of Example 11) has a solubility of> 8 mg / ml, and Racemic-SIP-PEG-7 (ie, the compound of Example 12) has a solubility of 30 mg / ml, Racemic-SIP-PEG-1000 (ie, the compound of Example 12). That is, it was shown that the solubility of the compound of Example 13)> 100 mg / ml and the solubility of racemic-SIP-PEG-2000 (that is, the compound of Example 14)> 100 mg / ml. It was concluded that as the PEG (ie-CH 2- CH 2- O-) chain length increased, the solubility became better.
本発明の化合物のSJSA−1ヌードマウス移植腫瘍の成長への阻害作用
1、実験目的
既知のキラル化合物としてのラセミ−SIP、本発明のキラル化合物であるラセミ−SIP−PEG−2(即ち、実施例8の化合物)、ラセミ−SIP−PEG−3(即ち、実施例9の化合物)、キラル−R−SIP−PEG−3(即ち、実施例11の化合物)、ラセミ−SIP−PEG−7(即ち、実施例12の化合物)、ラセミ−SIP−MPEG−2000(即ち、実施例14の化合物)のSJSA−1ヌードマウス移植腫瘍の成長への阻害作用を調べる。
2、実験動物
Balb/c/nuヌードマウス(体重15〜19g、雌)72匹は、北京華阜康バイオテクノロジー株式会社により提供された。証明書番号:SCXK(京)2014−0004。
3、実験用医薬品及び試薬
(1)医薬品
アドリアマイシン:陽性対照薬
ラセミ−SIP:(Org.Process Res.Dev.2013;17(2):247-256)乳白色の粉末;
ラセミ−SIP−PEG−2(即ち、実施例8の化合物):白色の粉末
ラセミ−SIP−PEG−3(即ち、実施例9の化合物):白色の粉末
キラル−R−SIP−PEG−3(即ち、実施例11の化合物):白色の粉末
ラセミ−SIP−PEG−7(即ち、実施例12の化合物):白色の粉末
ラセミ−SIP−MPEG−2000(即ち、実施例14の化合物):白色の粉末
(2)医薬品の調製方法
アドリアマイシン:滅菌生理食塩水で0.3mg/mlに調製し、投与用量を3.0mg/kg、投与体積を10ml/kgとした。
ラセミ−SIP:4%DMA、30%PEG400、66%(体積比)滅菌蒸留水を溶剤として濃度1.5mg/mlの溶液に調製し、投与用量を30.0mg/kg、投与体積を20ml/kgとした。
ラセミ−SIP−PEG−2:ポリオキシエチレンヒマシ油:95%エタノール:滅菌生理食塩水(体積比1.5:1.5:7)を溶剤として濃度が1.5mg/ml、3.0mg/mlの薬液に調製した。投与用量を15.0mg/kg、30.0mg/kg、投与体積を10ml/kgとした。
ラセミ−SIP−PEG−3:滅菌生理食塩水で濃度3.0mg/mlの薬液に調製した。投与用量を30.0mg/kgとした。投与体積を10ml/kgとした。
キラル−R−SIP−PEG−3:滅菌生理食塩水で濃度3.0mg/mlの薬液に調製した。投与用量を30.0mg/kgとした。投与体積を10ml/kgとした。
ラセミ−SIP−PEG−7:滅菌生理食塩水で濃度3.0mg/mlの薬液に調製した。投与用量を30.0mg/kgとした。投与体積を10ml/kgとした
ラセミ−SIP−MPEG−2000:滅菌生理食塩水で濃度5.0mg/mlの薬液に調製した。投与用量を50.0mg/kgとした。投与体積を10ml/kgとした。
(3)投与用量及び経路:
アドリアマイシンの用量を3.0 mg/kgとし、腹腔内注射により1日おきに1回、合計6回投与した。
ラセミ−SIPの用量を30.0 mg/kgとし、1日1回、週6回、合計9回胃内投与した。
ラセミ−SIP−PEG−2の用量を30.0mg/kgとし、腹腔内注射により1日1回、週6回、合計9回投与した。
ラセミ−SIP−PEG−3の用量を30.0mg/kgとし、腹腔内注射により1日1回、週6回、合計9回投与した。
キラル−R−SIP−PEG−3の用量を30.0mg/kgとし、腹腔内注射により1日1回、週6回、合計9回投与した。
ラセミ−SIP−PEG−7:用量を30.0mg/kgとし、腹腔内注射により1日1回、週6回、合計9回投与した。
ラセミ−SIP−mPEG−2000:用量を50.0mg/kgとし、腹腔内注射により1日1回、週6回、合計9回投与した。
(4)SJSA−1細胞:上海復祥バイオテクノロジー社から購入
(5)その他の試薬:ポリオキシエチレンヒマシ油(アラジン株式会社;CAS:61791−12−6)。
4、実験の手順
無菌条件で腫瘍細胞(SJSA−1)を収集し、滅菌生理食塩水で細胞密度が1×107個/mlとなるように調整し、ヌードマウスの脇の皮下に0.2mlを接種し、腫瘍が直径1cmの大きさに成長すると、無菌条件で摘出し、2.0mm×2.0mmの大きさの腫瘍塊に切り分け、ヌードマウスの脇の皮下に均一的に接種した。腫瘍体積が250mm3程度となると、9匹ずつ群分けて投与し(接種後8日目に)、腫瘍成長が不良な動物は除外された。対照群は、対照として生理食塩水を使用した。アドリアマイシン用量が3.0mg/kgの群、ラセミ−SIP用量が30.0mg/kgの群、ラセミ−SIP−PEG−2、ラセミ−SIP−PEG−3、キラル−R−SIP−PEG−3及びラセミ−SIP−PEG−7の用量がそれぞれ30.0mg/kgの群、ラセミ−SIP−MPEG−2000用量が50.0mg/kgの群とした。体重を週に3回秤量し、そして腫瘍の長さa及び幅bをノギスで測定し、式V=a×b2/2により腫瘍の体積を計算し、ここで、aが腫瘍の長さであり、bが腫瘍の幅である。接種後21日目に、ヌードマウスを頸椎脱臼により屠殺して撮影し、その後腫瘍を剥離し、重量を測定して撮影した。腫瘍のRTV(相対腫瘍体積)及び阻害率を計算した。同時に、ヌードマウスの末梢血を採取し、血球計数を行った。
5、データ処理
EXCELソフトで処理し、データを平均値±SDで表し、群間分析をt検定により統計的に処理した。
6、結果
(1)溶解度の剤形への影響
医薬品の調製方法より分かるように、ラセミ−SIP−PEG系化合物(実施例8、実施例9、実施例11、実施例12及び実施例14)は、水溶性がPEGを含まない化合物であるラセミ−SIPとラセミ−SIP−酸よりも優れ、また、PEG鎖長の増加につれて水溶性が向上し、実施例9、実施例11、実施例12及び実施例14は、水溶性が実施例8よりも優れ、そのまま生理食塩水に溶解することができ、静脈内投与により適し、経口薬による胃腸への副作用を避けることができる。
(2)腫瘍阻害率の評価
本発明の化合物は、PEGの含有によって、PEGを含まない化合物SIPよりも有意に強い腫瘍成長に対する阻害作用を示した。その中でも、ラセミ−SIP−PEG−2を30.0mg/kgの用量で注射により投与する場合は、PEGを含まないラセミ−SIPを経口投与する場合と比較して、やや優れた腫瘍成長に対する阻害作用を示した。ラセミ−SIP−PEG−3、キラル−R−PEG−3、ラセミ−SIP−PEG−7を30.0mg/kgの用量で、ラセミ−SIP−MPEG−2000を50.0mg/kgの用量で注射により投与する場合、PEGを含まないラセミ−SIPを経口投与する場合と比較して、より強い腫瘍成長に対する阻害作用を示した。相対腫瘍体積で阻害率を計算すると、ラセミ−SIP−PEG−2は55.36%、ラセミ−SIP−PEG−3は90.79%、キラル−R−PEG−3は97.9%、ラセミ−SIP−PEG−7は96.38%、ラセミ−SIP−MPEG−2000は96.02%であったが、経口投与の場合のSIPはわずか54.89%であった。腫瘍阻害率について、腫瘍重量で、それぞれ、ラセミ−SIP−PEG−2は50.55%、ラセミ−SIP−PEG−3は92.86%、キラル−R−PEG−3は97.84%、ラセミ−SIP−PEG−7は97.06%、ラセミ−SIP−MPEG−2000は96.70%であったが、経口投与の場合のSIPはわずか49.69%であった(表1、図7、8を参照)。各投与群は、その体重が生理食塩水対照群よりも低かったが、キラル−R−PEG−3投与群は、その体重が生理食塩水対照群よりも高く、且つ統計的に有意であった(表1、図9を参照)。スピロインドロンポリエチレングリコールカーボネート系化合物(SIP−PEG)は、その抗腫瘍活性が非エステル化スピロインドロン(SIP)よりも優れたとの結論が得られた。
(3)副作用の評価
各投与群の体重について、溶剤対照群と比較した結果、ラセミ−SIP−PEG−2では体重が約9.4%低下し、ラセミ−SIP−PEG−3では体重が約7.5%低下し、キラル−R−PEG−3では体重が約11%増加し、ラセミ−SIP−PEG−7では体重が約6.4%低下し、ラセミ−SIP−MPEG−2000では約5.2%低下したが、経口投与の場合のSIPでは約18%低下し、且つ統計学的に有意であった(表1、図7を参照)。このため、スピロインドロンポリエチレングリコールカーボネート系化合物(SIP−PEG)は、その毒性副作用が非エステル化スピロインドロン(SIP)よりも小さかったとの結論が得られた。
Inhibitory effect of the compound of the present invention on the growth of transplanted tumors of SJSA-1
2. Experimental animals 72 Balb / c / nu nude mice (body weight 15-19 g, female) were provided by Beijing Huafukang Biotechnology Co., Ltd. Certificate number: SCXK (K computer) 2014-0004.
3. Experimental drugs and reagents (1) Drugs Adriamycin: Positive control drug Racemic-SIP: (Org. Process Res. Dev. 2013; 17 (2): 247-256) Milky white powder;
Racem-SIP-PEG-2 (ie, compound of Example 8): white powder Racem-SIP-PEG-3 (ie, compound of Example 9): white powder Chiral-R-SIP-PEG-3 (ie, compound of Example 9) That is, the compound of Example 11): white powder racem-SIP-PEG-7 (that is, the compound of Example 12): white powder racem-SIP-PEG-2000 (that is, the compound of Example 14): white. (2) Preparation method of drug Adriamycin: Prepared to 0.3 mg / ml with sterile physiological saline, and the dose was 3.0 mg / kg and the dose volume was 10 ml / kg.
Racem-SIP: Prepared into a solution with a concentration of 1.5 mg / ml using 4% DMA, 30% PEG400, 66% (volume ratio) sterile distilled water as a solvent, and the administration dose was 30.0 mg / kg and the administration volume was 20 ml / ml. It was set to kg.
Racem-SIP-PEG-2: Polyoxyethylene castor oil: 95% ethanol: Sterilized saline (volume ratio 1.5: 1.5: 7) as a solvent with concentrations of 1.5 mg / ml and 3.0 mg / Prepared in ml of drug solution. The administration dose was 15.0 mg / kg, 30.0 mg / kg, and the administration volume was 10 ml / kg.
Racemic-SIP-PEG-3: Prepared as a drug solution having a concentration of 3.0 mg / ml with sterile physiological saline. The administration dose was 30.0 mg / kg. The administration volume was 10 ml / kg.
Chiral-R-SIP-PEG-3: Prepared as a drug solution having a concentration of 3.0 mg / ml with sterile physiological saline. The administration dose was 30.0 mg / kg. The administration volume was 10 ml / kg.
Racemic-SIP-PEG-7: Prepared as a drug solution having a concentration of 3.0 mg / ml with sterile physiological saline. The administration dose was 30.0 mg / kg. A mixture of racemic-SIP-PEG-2000: sterile physiological saline having an administration volume of 10 ml / kg was prepared to a concentration of 5.0 mg / ml. The dose was 50.0 mg / kg. The administration volume was 10 ml / kg.
(3) Administration dose and route:
The dose of adriamycin was 3.0 mg / kg, and it was administered by intraperitoneal injection once every other day for a total of 6 times.
The dose of racemic-SIP was 30.0 mg / kg, and the mixture was intragastrically administered once a day, 6 times a week, for a total of 9 times.
The dose of racemic-SIP-PEG-2 was 30.0 mg / kg, and it was administered by intraperitoneal injection once a day, 6 times a week, for a total of 9 times.
The dose of racemic-SIP-PEG-3 was 30.0 mg / kg, and it was administered by intraperitoneal injection once a day, 6 times a week, for a total of 9 times.
The dose of chiral-R-SIP-PEG-3 was 30.0 mg / kg, and it was administered by intraperitoneal injection once a day, 6 times a week, for a total of 9 times.
Racemic-SIP-PEG-7: The dose was 30.0 mg / kg, and the mixture was administered by intraperitoneal injection once a day, 6 times a week, for a total of 9 times.
Racemic-SIP-mPEG-2000: The dose was 50.0 mg / kg, and the mixture was administered by intraperitoneal injection once a day, 6 times a week, for a total of 9 times.
(4) SJSA-1 cells: purchased from Shanghai Revival Biotechnology Co., Ltd. (5) Other reagents: Polyoxyethylene castor oil (Aladdin Co., Ltd .; CAS: 61791-12-6).
4. Experimental procedure Tumor cells (SJSA-1) were collected under aseptic conditions, adjusted to a cell density of 1 × 10 7 cells / ml with sterile physiological saline, and subcutaneously placed on the side of a nude mouse. When 2 ml was inoculated and the tumor grew to a size of 1 cm in diameter, it was excised under aseptic conditions, cut into tumor masses having a size of 2.0 mm × 2.0 mm, and uniformly inoculated subcutaneously on the side of the nude mouse. .. When tumor volume is about 250 mm 3, (8 days after inoculation) administered separately group nine mice, tumor growth is bad animals were excluded. The control group used saline as a control. Adriamycin dose 3.0 mg / kg, racemic-SIP dose 30.0 mg / kg, racemic-SIP-PEG-2, racemic-SIP-PEG-3, chiral-R-SIP-PEG-3 and The racemic-SIP-PEG-7 dose was 30.0 mg / kg, respectively, and the racemic-SIP-PEG-2000 dose was 50.0 mg / kg. Weight were weighed three times a week, and the length a and width b of the tumors were measured with calipers, the tumor volume was calculated by the equation V = a × b 2/2 , where, a is a tumor length And b is the width of the tumor. On the 21st day after inoculation, nude mice were sacrificed by cervical spine dislocation and photographed, and then the tumor was exfoliated and weighed and photographed. Tumor RTV (relative tumor volume) and inhibition rate were calculated. At the same time, peripheral blood of nude mice was collected and blood cell count was performed.
5. Data processing The data was processed by EXCEL software, the data was represented by the mean value ± SD, and the intergroup analysis was statistically processed by t-test.
6. Results (1) Effect of solubility on dosage form As can be seen from the method for preparing pharmaceutical products, racemic-SIP-PEG-based compounds (Example 8, Example 9, Example 11, Example 12 and Example 14). Is superior in water solubility to the PEG-free compounds racem-SIP and racem-SIP-acid, and the water solubility improves as the PEG chain length increases, and Examples 9, 11, and 12 And Example 14 is more water-soluble than Example 8, can be dissolved in physiological saline as it is, is more suitable for intravenous administration, and can avoid side effects on the gastrointestinal tract due to oral preparations.
(2) Evaluation of Tumor Inhibition Rate The compound of the present invention showed a significantly stronger inhibitory effect on tumor growth than the PEG-free compound SIP due to the inclusion of PEG. Among them, when racemic-SIP-PEG-2 is administered by injection at a dose of 30.0 mg / kg, the inhibition against tumor growth is slightly superior to that when racemic-SIP containing no PEG is orally administered. Showed action. Racemic-SIP-PEG-3, Chiral-R-PEG-3, Racemic-SIP-PEG-7 at a dose of 30.0 mg / kg and Racemic-SIP-PEG-2000 at a dose of 50.0 mg / kg When administered by, it showed a stronger inhibitory effect on tumor growth as compared with the case where racemic-SIP containing no PEG was orally administered. When the inhibition rate was calculated based on the relative tumor volume, racemic-SIP-PEG-2 was 55.36%, racemic-SIP-PEG-3 was 90.79%, chiral-R-PEG-3 was 97.9%, and racemic. -SIP-PEG-7 was 96.38% and racemic-SIP-PEG-2000 was 96.02%, but SIP was only 54.89% when administered orally. Regarding the tumor inhibition rate, racemic-SIP-PEG-2 was 50.55%, racemic-SIP-PEG-3 was 92.86%, and chiral-R-PEG-3 was 97.84%, respectively, by tumor weight. Racemic-SIP-PEG-7 was 97.06% and Racemic-SIP-PEG-2000 was 96.70%, but SIP was only 49.69% when administered orally (Table 1, Figure). 7 and 8). Each treated group weighed less than the saline control group, while the chiral-R-PEG-3 treated group weighed more than the saline control group and was statistically significant. (See Table 1 and FIG. 9). It was concluded that the spiroindron polyethylene glycol carbonate compound (SIP-PEG) was superior in its antitumor activity to the non-esterified spiroindron (SIP).
(3) Evaluation of side effects As a result of comparing the body weight of each administration group with that of the solvent control group, the body weight of racemic-SIP-PEG-2 was reduced by about 9.4%, and that of racemic-SIP-PEG-3 was reduced by about 9.4%. 7.5% loss, chiral-R-PEG-3 gained about 11%, racemic-SIP-PEG-7 lost about 6.4%, racemic-SIP-PEG-2000 lost about about 6.4%. It decreased by 5.2%, but with SIP when administered orally, it decreased by about 18% and was statistically significant (see Tables 1 and 7). Therefore, it was concluded that the toxic side effect of the spiroindron polyethylene glycol carbonate compound (SIP-PEG) was smaller than that of the non-esterified spiroindron (SIP).
Claims (8)
(II)
一般式IIにおいて、Y1、Y2、Y3及びY4はそれぞれ独立してH及びハロゲンから選ばれ、R1はH及びC1−C5アルキル基から選ばれ、R2はH、C1−C5アルキル基及びC1−C5アルコキシ基から選ばれ、
nは3〜50の整数である。 A spiroindolone polyethylene glycol carbonate-based compound having a structure represented by the following general formula II, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
(II)
In General Formula II, Y 1 , Y 2 , Y 3 and Y 4 are independently selected from H and halogen, respectively, R 1 is selected from H and C1-C5 alkyl groups, and R 2 is H, C1-C5. Selected from alkyl and C1-C5 alkoxy groups,
n is an integer from 3 to 50.
ラセミ−12−オキソ−2,5,8,11,13−ペンタオキサペンタデカン−14−イル−4−((2’S,3R,4’S,5’R)−6−クロロ−4’−(3−クロロ−2−フルオロフェニル)−2’−ネオペンチル−2−オキソスピロ[ジヒドロインドール−3,3’−ピロリジン]−5’−カルボキサミド)−3−メトキシ安息香酸エステル、4
ラセミ体
キラル−12−オキソ−2,5,8,11,13−ペンタオキサペンタデカン−14−イル−4−((2’S,3R,4’S,5’R)−6−クロロ−4’−(3−クロロ−2−フルオロフェニル)−2’−ネオペンチル−2−オキソスピロ[ジヒドロインドール−3,3’−ピロリジン]−5’−カルボキサミド)−3−メトキシ安息香酸エステル、
キラル
ラセミ−24−オキソ−2,5,8,11,14,17,20,23,25−ノナオキサヘプタコサン−26−イル−4−((2’S,3R,4’S,5’R)−6−クロロ−4’−(3−クロロ−2−フルオロフェニル)−2’−ネオペンチル−2−オキソスピロ[ジヒドロインドール−3,3’−ピロリジン]−5’−カルボキサミド)−3−メトキシ安息香酸エステル、
ラセミ体
ラセミ−4−((2’S,3’R,4’S,5’R)−6−クロロ−4’−(3−クロロ−2−フルオロフェニル)−2’−ネオペンチル−2−オキソスピロ[ジヒドロインドール−3,3’−ピロリジン]−5’−カルボキサミド)−3−メトキシ安息香酸メトキシポリエチレングリコール1000カーボネート、
ラセミ体
ラセミ−4−((2’S,3’R,4’S,5’R)−6−クロロ−4’−(3−クロロ−2−フルオロフェニル)−2’−ネオペンチル−2−オキソスピロ[ジヒドロインドール−3,3’−ピロリジン]−5’−カルボキサミド)−3−メトキシ安息香酸メトキシポリエチレングリコール2000カーボネート、
ラセミ体
ラセミ−24−オキソ−2,5,8,11,14,17,20,23,25−ノナオキサヘプタコサン−26−イル−4−((2’S,3R,4’S,5’R)−6−クロロ−4’−(3−クロロフェニル)−2’−ネオペンチル−2−オキソスピロ[ジヒドロインドール−3,3’−ピロリジン]−5’−カルボキサミド)−3−メトキシ安息香酸エステル。
ラセミ体 The spiroindolone polyethylene glycol carbonate-based compound according to claim 1, wherein the spiroindolone polyethylene glycol carbonate-based compound is selected from the following compounds, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. ..
La Semi-12-oxo -2,5,8,11,13- penta-oxa-pentadecane-14-yl -4 - ((2'S, 3R , 4'S, 5'R) -6- chloro-4 ' -(3-Chloro-2-fluorophenyl) -2'-neopentyl-2-oxospiro [dihydroindole-3,3'-pyrrolidine] -5'-carboxamide) -3-methoxybenzoic acid ester, 4
Racemic chiral-12-oxo-2,5,8,11,13-pentaoxapentadecane-14-yl-4-((2'S, 3R, 4'S, 5'R) -6-chloro-4 '-(3-Chloro-2-fluorophenyl) -2'-neopentyl-2-oxospiro [dihydroindole-3,3'-pyrrolidine] -5'-carboxamide) -3-methoxybenzoic acid ester,
Chiral racem-24-oxo-2,5,8,11,14,17,20,23,25-nonaoxaheptacosan-26-yl-4-((2'S, 3R, 4'S, 5'R) ) -6-Chloro-4'-(3-chloro-2-fluorophenyl) -2'-neopentyl-2-oxospiro [dihydroindole-3,3'-pyrrolidine] -5'-carboxamide) -3-methoxybenzoic acid Acid ester,
Racemic Racemic-4-((2'S, 3'R, 4'S, 5'R) -6-chloro-4'-(3-chloro-2-fluorophenyl) -2'-neopentyl-2- Oxospiro [dihydroindole-3,3'-pyrrolidine] -5'-carboxamide) -3-methoxybenzoate methoxypolyethylene glycol 1000 carbonate,
Racemic Racemic-4-((2'S, 3'R, 4'S, 5'R) -6-chloro-4'-(3-chloro-2-fluorophenyl) -2'-neopentyl-2- oxospiro [dihydroindole-3,3'-pyrrolidin] -5'-carboxamido) -3-methoxybenzoic acid methoxy polyethylene glycol 2000 Kabone DOO,
Racemic body
La Semi-24-oxo -2,5,8,11,14,17,20,23,25- nona oxa hept co San -26- yl -4 - ((2'S, 3R , 4'S, 5 ' R) -6-Chloro-4'-(3-chlorophenyl) -2'-neopentyl-2-oxospiro [dihydroindole-3,3'-pyrrolidine] -5'-carboxamide) -3-methoxybenzoic acid ester.
Racemic body
(III)
(IV)
ここで、Y1、Y2、Y3、Y4、R1、R2及びnは請求項1と同義であり、R3はネオペンチル基である。
The spiroindolone-based compound represented by the following general formula III and the compound represented by the following general formula IV are subjected to a nucleophilic substitution reaction in the presence of a base to cause the spiroindolone polyethylene glycol carbonate-based compound. The method for producing a spiroindolone polyethylene glycol carbonate-based compound according to claim 1, which comprises a step of obtaining a compound.
(III)
(IV)
Here, Y 1 , Y 2 , Y 3 , Y 4 , R 1 , R 2 and n are synonymous with claim 1, and R 3 is a neopentyl group.
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US8222288B2 (en) | 2006-08-30 | 2012-07-17 | The Regents Of The University Of Michigan | Small molecule inhibitors of MDM2 and the uses thereof |
US8088815B2 (en) | 2009-12-02 | 2012-01-03 | Hoffman-La Roche Inc. | Spiroindolinone pyrrolidines |
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AU2012253339B2 (en) | 2011-05-11 | 2016-03-31 | Sanofi | Spiro-oxindole MDM2 antagonists |
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CA2926307C (en) * | 2013-12-05 | 2021-11-16 | F. Hoffmann-La Roche Ag | Novel combination treatment for acute myeloid leukemia (aml) |
CA2958193C (en) * | 2014-08-18 | 2024-02-27 | Hudson Biopharma Inc. | Spiropyrrolidines as mdm2 inhibitors |
-
2016
- 2016-08-08 JP JP2019507118A patent/JP6848047B2/en active Active
- 2016-08-08 EP EP16911933.6A patent/EP3498712B1/en active Active
- 2016-08-08 US US16/324,034 patent/US10471154B2/en active Active
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EP3498712A4 (en) | 2020-01-22 |
JP2019524803A (en) | 2019-09-05 |
EP3498712B1 (en) | 2024-01-03 |
WO2018027477A1 (en) | 2018-02-15 |
US10471154B2 (en) | 2019-11-12 |
EP3498712C0 (en) | 2024-01-03 |
EP3498712A1 (en) | 2019-06-19 |
US20190209700A1 (en) | 2019-07-11 |
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